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Bone dysplasias in man: molecular insights
301
Bone dysplasias in man: molecular insights Clair A Francomano*, lain Mclntosht and Douglas J Wilkin$ The recent explosion in the number of identified genes involved in the human skeletal dysplasias has dramatically advanced this particular field. While linkage efforts are mapping hereditary disorders of the skeleton at an ever accelerating pace, progress in the Human Genome Project is providing tools for rapid gene discovery after the map location is known. Emerging themes in the molecular analysis of the skeletal dysplasias include the identification of allelic series of disorders and the existence of mutational and genetic heterogeneity in many of these conditions. Allelic series include those conditions caused by mutations in the genes encoding type II collagen (CQL2A1), cartilage oligomeric matrix protein (COMP),fibroblast growth factor receptor 3 (FGFRJ) and the diastrophic dysplasia sulfate transporter (DTDST). The recognition of these phenomena has initiated the analysis of the relationship between disease phenotype and gene.
Addresses
*$Medical Genetics Branch, National Center for Human Genome Research, National Institutes of Health, Bethesda, Maryland 20892,
USA *e-mail: [email protected] ~e-mail: Dwilkin@ nchgr.nih.gov tCenter for Medical Genetics, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Block 1012G Baltimore, Maryland 21287, USA; e-mail: [email protected] Current Opinion in Genetics & Development 1996, 6:301-308
© Current Biology Ltd ISSN 0959-437X Abbreviations achondrogenesis type IB ACG IB atelosteogenesis type II AO II
COMP DTD DTDST FGFR MED NC1 NC2 PSACH SED SEMD SMCD
cartilage oligomeric matrix protein diastrophic dysplasia diastrophic dysplasia sulfate transporter fibroblast growth factor receptor multiple epiphyseal dysplasia carboxy-terminal non-collagenous domain amino-terminal non-collagenous domain pseudoachondroplasia spondyloepiphyseal dysplasia spondyloepimetaphyseal dysplasia Schmid metaphyseal chondrodysplasia
Introduction The skeletal dysplasias are a heterogeneous group of disorders that we have only recently begun to understand at the molecular level. Although the clinical delineation of the skeletal dysplasias began in the mid-1960s, and biochemical and molecular analyses of type I collagen in osteogenesis imperfecta were well advanced in the 1980s, little was known about the genes underlying the remaining skeletal dysplasias when the current decade began. Advances in map-based gene discovery have enabled enormous progress in the past 2-3 years. The identification
of specific genes (Table 1), mutations, and (increasingly) genotype-phenotype relationships lend promise to a greater understanding of skeletal development in the years ahead. Specifically, recent advances include the mapping of multiple disorders for which the specific genes have not yet been identified. In addition, a number of disease-linked genes have been identified, including those for pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (MED) [1",2"°], Schmid metaphyseal chondrodysplasia (SMCD) [3], Jansen metaphyseal chondrodysplasia [4"'], diastrophic dysplasia (DTD) [5°°], atelosteogenesis type II (AO II) [6"°], and achondrogenesis type IB (ACG IB) [7°']. The past few years have also witnessed the inclusion of Kniest dysplasia [8] and spondyloepimetaphyseal dysplasia (SEMD) of the Strudwick type [9 °] in the list of type II collagen disorders and the identification of a second gene linked with Stickler syndrome [10 °°] (Table 1). Perhaps the greatest excitement surrounding the recent advances in skeletal dysplasia research has centered around achondroplasia--the most common human skeletal dysplasia--and its related disorders, hypochondroplasia and thanatophoric dysplasia. These conditions--along with the craniosynostosis syndromes that include Pfeiffer syndrome, Apert syndrome, Crouzon syndrome, Crouzon syndrome with Acanthosis-Nigricans [11"*], and JacksonWeiss syndrome--have been shown to be caused by mutations in the fibroblast growth factor receptor (FGFR) gene family. A considerable amount of literature has been published on FGFR mutations in the achondroplasia family of disorders and the craniosynostoses over the past 2 years; we refer the reader to a number of recent reviews [12°°-14°°]. In addition, many reviews have been written on the disorders of collagens types I and II, including osteogenesis imperfecta types I-IV, and the Ehlers-Danlos syndromes and, therefore, these disorders will not be discussed here [15-171. In this review, we concentrate on those genes which have recently been shown to play important roles in skeletogenesis, including those encoding collagen types II, IX, X, and XI, the diastrophic dysplasia sulfate trasnporter, and cartilage oligomatrix protein. Type X c o l l a g e n a n d S c h m i d m e t a p h y s e a l dysplasia
Type X collagen is the product of a condensed gene, COL1OA1, which contains only two introns, and thus is substantially smaller than those genes encoding fibrillar collagens. The first exon is non-coding, the second encodes the signal peptide and part of the amino-terminal non-collagenous domain (NC2), and the third encodes the
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Genetics of disease
Table 1 Disease-linked genes for skeletal dysplasia and related disorders. Gene
Diseases
References
COL 1A I
Osteogenesis imperfecta types I-IV, and Ehlers-Danlos syndrome type VII
[15] [17]
COL 1A2
Osteogenesis Imperfecta types I-IV, and Ehlers-Danlos syndrome type VII
[15] [17]
COL3A 1
Ehlers-Danlos syndrome type IV
[16]
COL5A 1
Ehlers-Danlos syndrome type II
[54,5?]
COL2A 1
Achondrogenesis type II, hypochondroplasia, Kniest dysplasia, Spondyloepi(meta)physeal dysplasia, Stickler syndrome and osteoarthritis with mild SED
[26"] [26"'] [8,26"] [9",26 "°] [26"] [26 "°]
COL9A2
Multiple epiphyseal dysplasia
COLIOA1
Schmid metaphyseal chondrodysplasia
[3]
COL11A2
Stickler syndrome and OSMED
[10"] [10"]
COMP
Pseudoachondroplasia and multiple epiphyseal dysplasia
[1 "*,2"*] [2"]
DTDST
Diastrophic dysplasia, atelosteogenesis type II and achondrogenesis type IB
[5"'] [6"] [7"]
PTH-PTHrP receptor
Jansen metaphyseal chondrodysplasia
[4"]
SOX9
Campomelic dysplasia
[55"]
Arylsulfatase E
Chondrodysplasia punctata
[53"']
CDMP- 1
Acromesomelic chondrodysplasia (Hunter-Thompson type)
[56"]
[53"]
Achondroplasia, Thanatophoric dysplasia (types 1 and 2), Hypochondroplasia and Crouzon syndrome with Acanthosis-Nigricans
[12"-14"]
FGFR2
Crouzon syndrome, Apert syndrome, Jackson-Weiss syndrome and Pfeiffer syndrome
[12"-14"] [12"-14"*] [12"-14"] [12"-14"]
FGFR1
Pfeiffer syndrome
[12--14 °°]
FGFR3
[12"-14"] [12"-14"*] [11 "]
remainder of NC2, the entire collagenous domain and the carboxy-terminal non-collagenous domain, NC1 [18]. COLIOA1 has been implicated in the etiology of Schmid metaphyseal chondrodysplasia (SMCD), a rare autosomal dominant disorder causing short stature; abnormal distal tibial metaphyses with anterior cupping and splaying and
sclerosis of the ribs arc considered diagnostic of this disease. As in other metaphyseal dysplasias, growth plate histology shows dense collagen surrounding clusters of hypertrophic cells extending into the metaphyses [19]. In a large Mormon kindred with SMCD, Watman eta/. [3] have found a 13bp deletion in the NC1 domain of COLIOA1 segregating with the disorder. Over 20 additional mutations have been identified in the COLIOA1 genes of SMCD patients, each within the NC1 domain [20*-22",231. Approximately half the mutations are single amino acid substitutions, and the remainder are frameshift or nonsense mutations, leading to premature termination of the polypeptide (although equimolar amounts of the normal and mutant transcript, and probably protein monomers, are expected as these premature termination codQns are in the terminal exon). It has been suggested that the mutant polypeptides are unable to participate in trimer formation as trimerization is initiated at the carboxy-terminal end of the protein. The relatively mild SMCD phenotype could be due to the reduction in the amount of normal type X collagen deposited in the exttacellular matrix. This hypothesis is supported by in vitro expression studies in which type X collagen carrying a SMCD mutation neither self-assembled nor interacted with normal monomeric polypeptides [241. An alternative mechanism is that SMCD is the resuh of a dominant negative effect of the mutant polypeptide on normal function. This hypothesis is supported by the observation that mice whose endogenous Co/l&ll genes are inactivated do not have any demonstrable abnormal phenotype up to 3 months of age, in either the heterozygous or homozygous state [25]. Given the presumed role of type X collagen in endochondral ossification, a normal phenotype in the absence of the protein is surprising. It should be noted, however, that the lack of a phenotype in these Co/l&d-null mice may be the result of species-specific differenccs in type X collagen function or anatomical differences that allow mice to compensate for the absence of the protein. Furthermore, the concentration of mutations within the NCI domain cannot be taken as supporting a haplo-inst, fficiency model as the level of COLIOA1 transcript could be redticed by mutations elsewhere in the gene; such mutations have not been identified, despite the efforts of many investigators. This point is reviewed extensively by Wallis eta/. [23]. T y p e II c o l l a g e n d i s o r d e r s a n d r e l a t e d diseases The type II collagen disorders are a phenotypically heterogeneous group of conditions which affect predominantly the skeletal and visual systems (see Fig. 1). Known type II collagen disorders include achondrogenesis type II, hypochondrogenesis, Kniest dysplasia, a number of types of spondyloepiphyscal dysplasia (SED), SEMD, Stickler syndrome, and osteoarthritis with mild SED [26°']. Recent significant findings in this area include the confirmation of genetic heterogeneity in Stickler syndrome by the
Bone dysplasiasin man Francomano, Mclntosh
and Wilkin
303
facies, progressive myopia and cleft palate [27]. A number of COL2A1 mutations have been identified in individuals with Stickler syndrome and, interestingly, all except one result in premature termination codons [28-32].
identification of a second Stickler syndrome gene and the inclusion of Kniest dysplasia in this list of disorders.
Stickler syndrome Stickler syndrome is one of the milder type II collagen disorders. As is the case in many autosomal dominant disorders, the phenotype is variable. Affected individuals may exhibit mild spondyloepiphyseal dysplasia, premature osteoarthritis, joint hypermobility, hearing loss, a specific
Genetic heterogeneity has been reported for this disorder on the basis of linkage observations [33-35]. Type II collagen is closely associated with both type IX collagen and type XI collagen in cartilage collagen fibrils in
Figure 1 Type II collagendisorders G 574-'-S
G691~R
G817-*V
G943~S
Disorder AII-H
5' i
R?5-*C
G175--'R
~ SED
R 519~C
256-73
G853--'E G910--*C 604-621
964-99
R
5' i
875-?* G274~S G154--,R
SEMD
G 709--,C
G997~S
5' I
I
G304-*C
91-108~4-41 5' I
U
102-8
Stickler
97O-84*
R789-~C
G292-*V
G103--*D
Kniest
I
U
2~6 -73
~
G841--~S
36~78
1007-12
NI
U
142-56 274-9 223-55
5' Q Q
Q
Q
QQ
QI
'~ 1996 Current Opinion in Genetics & Development
Substitution
Deletion
Duplication
Stop codon
O A schematic diagram illustrating the location of COL2A1 mutations that lead to collagen II disorders: achondrogenesis type II-hypochondrogenesis (All-H), spondyloepiphyseal dysplasia (SED), spondyloepimetaphyseal dysplasia (SEMD), Kniest dysplasia and Stickler syndrome. The COL2A 1 gene is represented by a horizontal light-shaded bar. Mutations resulting in amino acid substitutions (open arrows), deletions (darker shaded boxes), duplications (asterisks), and stop codons (hexagons) are shown. The residue numbers of the mutated bases in the collagen triple helix are indicated. As the recognition of COL2A1 mutations is a rapidly evolving process, the authors have not attempted to include all known mutations. (Original figure courtesy of Daniel Cohn and Geert Mortier.)
304 Geneticsof disease
the extracellular matrix. This k n o w l e d g e - - t o g e t h e r with information on the chondrodysplasia mouse (see review by S Darling, ths issue [pp 289-294])--prompted Brunner et al. [36 °°] to examine genes encoding collagen types IX and XI in Stickler syndrome families in which the phenotype was not linked to COL2A1. T h e y found linkage of the Stickler syndrome phenotype to 6p22-p21.3, the region where C O L l l A 2 maps, in a large Dutch family. Subsequently, Vikkula et al. [10"*] have found a C O L l l A 2 exon skip mutation in this family. Interestingly, disease-affected individuals in this Stickler syndrome family lack the significant ocular deformities characterisitic of the disease, which are present in the majority of affected persons from families linked to COL2A1 [37*]. This may be explained by the fact that in the eye vitreous fluid, the product of the C O L l l A 2 gene is replaced in the collagen XI fiber by the product of the COL5A2 gene [38].
Otospondylomegaepiphyseal dysplasia syndrome In their study, Vikkula et al. [10 "°] also found a C O L l l A 2 mutation in a family with otospondylomegaepiphyseal dysplasia syndrome, an autosomal recessive disorder characterized by spondyloepiphyseal dysplasia and sensorineural hearing loss. Affected children in this family were homozygous for the mutation, a G--~A transition, resulting in a Gly-+Arg amino acid substitution in the triple helical domain of the protein, whereas unaffected children were heterozygous for the mutation.
Kniest dysplasia In a family that proved to be highly instructive, a woman with Stickler syndrome had a daughter with Kniest dysplasia, a much more severe skeletal dysplasia with extreme short stature and profound joint involvement [8]. T h e mutation was a 28 bp deletion spanning the COL2A1 exon 12-intron 12 junction, resulting in the skipping of exon 12. T h e mother was found to be a somatic mosaic for this m u t a t i o n - - t h e first Stickler COL2A1 mutation that is not a premature termination codon. Moreover, this was the first mutation identified in an individual with Kniest dysplasia and added the phenotype to the growing list of type II collagen disorders. Additional COL2A1 mutations have been identified recently in individuals with Kniest dysplasia ([39*,40",41]; DJ Wilkin et a/., Am J Hum Genet 1993, $3:A210; GR Mortier et al., Am J Hum Genet 1995, 87:A221). All of these mutations, except for one, are either small deletions or result in exon skipping in type II collagens; one mutation found in two unrelated individuals resulted in a deletion of seven amino acids encoded by exon 12 [39"]. T h e exception is a Glyl03-+Asp substitution, resulting in the substitution of a glycine residue encoded by exon 12, which is deleted in three other individuals with Kniest dysplasia [40*]. Mutational patterns seem to be emerging in some of the type II collagen phenotypes, s u c h as premature termination codons resulting in Stickler syndrome and small deletions around exon 12 resulting predominantly in Kniest
dysplasia. Further delineation on the genotype-phenotype relationships will await the recognition of additional mutations.
The dystrophic dysplasia sulfate transporter disorders D T D , AO II, and ACG IB are all severe autosomal recessive skeletal dysplasias that have recently been found to result from mutations in the diastrophic dysplasia sulfate transporter (DTDST) gene [5**-7 °'] demonstrating another allclic series of disorders resulting from mutations in a single gene.
Diastrophic dysplasia D T D is recognized at birth by a severe club foot deformity and an abducted 'hitchhiker' thumb. Patients also have profound short-limbed dwarfism, joint dysplasia, and kyphoscoliosis (deformation of the spine). Malformed pinnae of the ear with calcification of the cartilage is another characteristic of this disease. H~stbacka et al. [42] stated that 160 patients with D T D have been diagnosed in Finland, suggesting a founder effect. In a separate study, H~stbacka and her colleagues [5"'] have used this superb source of related families with D T D for the positional cloning of the D T D gene by fine structure linkage disequilibrium mapping. The gene was found to encode a novel sulfate transporter. Impaired function of this transporter would be expected to lead to the undersulfation of proteoglycans in the cartilage extracellular matrix, resulting in the disease phenotype. Although the single mutation responsible for the great majority of D T D alleles found in affected Finnish individuals has not yet been found, point mutations have been localized in non-Finnish patients [5*']. One mutation, a single-base deletion in codon 575, creatcs a frameshift and premature termination codon after nine codons which would eliminate 20% of the encoded protein. Three D T D patients from the Netherlands, France, and Germany were found to carry this particular mutation.
Atelosteogenesis type II AO II--charactcrized by severely shortened limbs, small chest, scoliosis, club foot, abducted thumbs and great toes, and cleft p a l a t e - - i s lethal in the newborn period. Histologically, cartilage collagen in incidences of AO II, is clumped and deficient--similar to the cartilage appearance in D T D . As a result of the clinical and histological similarities between AO II and D T D , a shared pathogenesis involving the same biochemical pathway and possibly the same gene was postulated. T h e identification of the D T D S T gene allowed investigation of the hypothesis that these diseases are related genetically. Cultured skin fibroblasts from three patients with AO II have been found to be defective in sulfate transport and sulfation of proteoglycans [6"']. Five D T D S T mutations, accounting for the six AO II alleles in these
Bone dysplasiasin man Francomano,Mclntoshand Wilkin 305
patients, were identified. One of these mutations, found in two unrelated AO II probands as a single base pair deletion (-adenosine, nucleotide 1751), has also been identified in three unrelated D T D patients and one ACG IB patient. T h e other mutation in one of the AO II patients was a C--+T transition at nucleotide 862, resulting in an Arg279--)Trp amino acid substitution. This mutation was also found in four D T D chromosomes. T h e AO II mutations are in the coding regions of the protein, resulting in late frameshift or missense mutations [7°°].
hands and scoliosis (lateral deformation of the spine); radiographically, metaphyseal and epiphyseal abnormalities of the hands and long bones and anterior beaking of the vertebrae are also apparent. M E D is characterized by abnormalities in the epiphyseal centers of the knees, hands, shoulders, and hips. Radiographical and histological similarities between these two conditions led to the hypothesis that they are part of the same bone dysplasia family [44] and are perhaps the result of mutations in the same gene.
Achondrogenesis IB ACG IB of the Parenti-Fraccaro type is an autosomal recessive disorder in which affected individuals are either stillborn or die within minutes of birth, and it is the most severe of these three D T D S T gene disorders. Superti-Furga [43] found a reduced amount of proteoglycans in cartilage of patients with ACG lB. He further demonstrated that these proteoglycans were synthesized normally but were not sulfated and suggested that such a finding could be explained by deficent activity of one of the enzymes responsible for the biological activity of sulfate. Recently, Superti-Furga et al. [7°°] have identified additional sulfate defects in ACG IB probands and found six different mutations in the D T D S T gene from 11 of 12 ACG IB alleles, with one of the mutations (-adenosine, nucleotide 1751) previously identified in D T D and AO II patients. Of the ACG IB probands studied to date, all have mutations in the coding regions of both strands, with most leading to premature termination codons [6",7°°].
Cartilage oligomeric matrix protein ( C O M P ) - - a member of the thrombospondin family of extracellular calcium binding p r o t e i n s - - i s a pentameric glycoprotein of the cartilage extracellular matrix found in the territorial matrix surrounding chondrocytes [45]. T h e human COMP gene has recently been mapped to chromosome 19p13.1 [46]. Linkage studies have placed PSACH [47,48] and M E D [49 °] in the same chromosomal region, making the COMP gene an ideal candidate to screen for mutations in these two disorders. Recently, Hecht et al. [1"*] and Briggs et al. [2"°1 have reported mutations in the COMP gene in individuals with PSACH. Hecht etal. [1 °°] identified a loss of a conserved aspartate residue from a calmodulin-like repeat encoded by cxon 13B in five unrelated patients with PSACH (as well as three other mutations) and Briggs etal. [2"'] found a three base pair deletion in exon 10 of the COMP gene, which eliminated an aspartic acid codon from the fourth calmodulin-like repeat of COME Cohn and colleagues [2"*,50] have also identified additional exon 10, exon 11, and exon 13 mutations in PSACH patients, and exon 10 and exon 11 mutations in M E D (Fairbanks type) sporadic patients and families--confirming the allclic relationship between these related phenotypes .
These new findings once again define a family of diseases which results from defects in a single gene. It has been proposed that the differences in severity of these three phenotypes results from amount of residual D T D S T protein activity present, with ACG IB representing the null phenotypc with complete loss of function, AO II representing a partial loss of function, and D T D representing an even milder loss of function [6"']. This theory is supported by the findings that no D T D probands have two mutations in the coding region of DTDST, whereas the AO II mutations are in the coding regions of the protein--resulting in late frameshift or missense m u t a t i o n s - - a n d the ACG IB probands always have mutations in the coding regions of both alleles, with most leading to premature termination codons [5*°-7"°]. Identification of the Finnish mutation, which accounts for such a great number of D T D probands, will aid in the explication of the relationship between phenotype and mutation type in this family of disorders.
Cartilage o l i g o m e d c matrix protein and type I X collagen PSACH and M E D are autosomal dominant forms of short-limbed dwarfism. PSACH is characterized by short stature, which is recognized in early childhood, short
In families where the M E D phenotype was not linked to COME Briggs et al. [51"] demonstrated linkage of the phenotype to the region of chromosome 1 containing COLgA2, which encodes the ~-2 chain of the type IX collagen. This observation confirmed genetic heterogeneity in MED. More recently, Muragaski et al. [52"*] have found a COLgA2 splice site mutation resulting in exon skipping in a Dutch family with MED, thus confirming both the genetic heterogeneity of the disorder and a role for COLgA2 in the cause of MED.
Conclusions Recent findings in the studies of skeletal dysplasias have, as a common theme, the existence of allelic series with related disorders resulting from distinct mutations in the same gene. This phenomenon has been described for the genes encoding the FGFRs, type I collagen, type II collagen, type XI collagen, D T D S T , and COME T h e identification of novel components of the extracellular matrix will lead to the identification of additional disease genes, and eventually the understanding of how these components interact with each other during both normal and aberrant skeletogenesis.
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References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as: • ••
of special interest of outstanding interest
1. ••
Hecht JT, Nelson LD, Crowder E, Wang Y, Elder FFB, Harrison WR, Francomano CA, Prange CK, Lennon GG, Deere M, Lawler J: Mutations in exon 17B of cartilage oligomeric matrix protein (COMP) cause pseudoachondroplasia. Nat Genet 1995, 10:325-329. This paper (and [2°°]) describes the first COMP mutations found in PSACH. Using the candidate gene approach, the authors identified mutations in eight familial and isolated PSACH cases, all in exon 1 ?B (corresponding to exon 13 of [2°°]). Six of the mutations delete or change a well- conserved aspartic acid residue within the calcium binding repeats. 2. ••
Briggs MD, Hoffman SMG, King LM, Olsen AS, Mohrenweiser H, Leroy JG, Mortier GR, Rimoin DL, Lachman RS, Gaines ES et al.: Pseudoachondroplasia and multiple epiphyseal dysplasia due to mutations in the cartilage ollgorneric matrix protein gene. Nat Genet 1995, 10:330-336. This paper (and [1°°]) describes the first COMP mutations identified in PSACH, as well as the first MED mutations in COMP, demonstrating that PSACH and some forms of MED are allelic. The mutations identified, as with those described in [1°°], are in the calcium binding domain. 3.
Warman ML, Abbott M, Apte SS, Hefferon TW, Mclntosh I, Cohn DH, Hecht JT, Olsen BR, Francomano CA: A mutation in the human type X collagen gene in a family with Schmid rnetaphyseal chondrodysplasia. Nat Genet 1993, 5:?9-82.
Schipani E, Krusw K, J~ippner H: A constitutively active mutant PTH-PTHrP receptor in Jansen-type metaphyseal chondrodysplasia. Science 1995, 268:98-100. The authors describe a mutation in the parathyroid hormone-parathyroid hormone-related peptide receptor in a patient with Jansen-type metaphyseal dysplasia. The authors suggest that their findings explain the abnormal formation of endochondral bone in this rare short-limbed dwarfism.
osteochondrodysplaslas associated with the COL11A2 locus. Cell 1995, 80:431-437 This paper identifies COL 11A2 mutations in a Stickler syndrome (dominant) family and OSMED (recessive) family. These are the first two phenotypes found to result from mutations in type XI collagen. The observations reported here establish COL11A2 as a second locus causing Stickler syndrome. The authors propose a molecular mechanism for differences in the ocular phenotype between Stickler syndrome caused by COL2A1 mutations, and those caused by COL11A2. 11. **
Meyers GA, Orlow SJ, Munro IR, Przylepa KA, Jabs EW: Fibroblast growth receptor 3 (FGFR3) transrnembrane mutation in Crouzon syndrome with acanthosis nigricans. Nat Genet 1995, 11:462-464. The authors identify mutations in FGFR3 in a disease outside the aehondroplasia spectrum (including thanatophoric dysplasia and hypochondroplasia), demonstrating locus heterogeneity in Crouzon syndrome and expanding the phenotypic spectrum resulting from mutations in FGFR3. 12. See 13. **
Park V~J, Bellus GA, Jabs EW: Mutations in fibroblast growth factor receptors: phenotypic consequences during eukaryotic development. Am J Hum Genet 1995, 57:748-745. See annotation [14°']. 14. Winter RM: Recent molecular advances in dysrnorphology. eo Hum Mol Genet 1995, 4:1699-1 ?04. Together with [12 °°] and [13°°], this review provides an excellent description of recent findings of human developmental disorders, including phenotypes resulting from mutations in the FGFRs. 15.
Byers PH: Osteogenesis irnperfecta. In Connective Tissue and its Heritable Disorders. Edited by Royce PM, Steinmann B. New York: Witey-Liss; 1993:31 ?-350.
16.
DePaepe A: Ehlers-Danlos syndrome type IV. Clinical and molecular aspects and guidelines for diagnosis and management. Dermatology 1994, 189:21-25.
17,
Byers PH: Ehlers-Danlos syndrome: recent advances and current understanding of clinical and genetic heterogeneity. J Invest Dermatol 1994, 103:47S-52S.
18.
Thomas JT, Cresswell CJ, Rash B, Nicolai H, Jones T, Solomon E, Grant ME, Boot-Handford RP: The human collagen X gene. Complete primary translated sequence and chromosomal localization. Biochem J 1991, 280:617-623.
19.
Lachman RS, Rimoin DL, Spranger J: Metaphyseal chondrodyspiasia, Schmid type. Clinical and radiographic delineation with a review of the literature. Pediatr Radio/1988, 18:93-102.
4. •*
5. ••
H~stbacka J, De la Chapetle A, Mahtani MM, Clines G, ReeveDaly MP, Daly M, Hamilton BA, Kusumi K, Trivedi B, Weaver A et aL: The diastrophic dysplasia gene encodes a novel sulfate transporter: positional cloning by fine-structure linkage disequilibrium mapping. Ceil 1994, 78:1073-108'7. A fascinating paper describing the identification of a novel sulfate transporter gene and the identification of mutations in this gene in individuals with DTD. The authors use linkage disequilibrium mapping to identify the gene, capitalizing on the high carrier frequency in the Finnish population. 6. ••
H&stbacka J, Superti-Furga A, Wilcox WR, Rimoin DL, Cohn DH, Lander ES: Atelosteogenesis type II is caused by mutations in the diastrophic dysplasia sulfate-transporter gene (DTDST): evidence for a phenotypic series involving three chondrodysplasias. Am J Hum Genet 1996, 58:255-262. The authors identify the first mutations in AO II, also in the DTDST gene, adding this phenotype to the list of diseases that result from DTDST mutations. 7. ••
Superti-Furga A, Hastbacka J, Wilcox WR, Cohn DH, Van der Harten HJ, Rossi A, Blau N, Rimoin DL, Steinman B, Lander ES, Gitzelmann R: Achrondrogenesis type IB is caused by mutations in the diastrophic dysplasia sulphate transporter gene. Nat Genet 1996, 12:100-102. This paper completes (to date) the list of phenotypes caused by mutations in the DTDSTgene. ACG IB is the most severe of the three disorders due to DTDST mutations and extends the phenotypic spectrum of disease at this locus. 8.
Winterpacht A, Hilbert M, Schwarze U, Mundlos S, Spranger J, Zabel BU: Kniest and Stickler dysplasia phenotypes caused by collagen type II gene (COL2AI) defect. Nat Genet 1993, 3:323-326.
Tiller GT, Polumbo PA, Weis MA, Bogaert R, Lachman RS, Cohn DH, Rimoin DL, Eyre DR: Dominant mutations in the type II collagen gene, COL2A1, produce spondyloepirnetaphyseal dysplasia, Strudwick type. Nat Genet 1995, 11:87-89. This paper identifies COL2A 1 mutations in the Strudwick type of SEMD and adds this phenotype to the list of type II collagen disorders. This phenotype includes dappled metaphyses, which are not seen in SED.
20. •
Mclntosh I, Abbot MH, Warrnan ML, Olsen BR, Francomano CA: Additional mutations of type X collagen confirm COLIOA1 as the Schmid metaphyseal chondrodysplasia locus. Hum Mol Genet 1994, 3:303-307. See annotation [22*]. 21. •
Wallis GA, Rash B, Sweetman WA, Thomas JT, Super M, Evans G, Grant ME, Boot-Handford RP: Amino acid substitutions of conserved residues in the carboxy-terminal domain of the alpha-I(X) chain of type X collagen occur in two unrelated families with rnetaphyseal dysplasia type Schrnid. Am J Hum Genet 1994, 54:169-178. See annotation [22°]. 22. •
Mclntosh I, Abbot MH, Francomano CA: Concentration of mutations causing Schmid metaphyseal chondrodysplasia in the C-terrninal noncollagenous domain of type X collagen. Hum Mutat 1995, 5:121-125. Here we identified additional COLIOA1 mutations which result in the Schmid phenotype. Along with those described in [20",21"], all of the mutations are in the NO1 domain of the protein, suggesting that the mutant chains cannot participate in chain association and trimer formation. 23.
Wallis GA, Rash B, Sykes B, Bonaventure J, Maroteaux P, Zabel B, Wynne-Davis R, Grant ME, Boot-Handford RP: Mutations within the gene encoding the ~l(X) chain of type X collagen (COLIOA1) cause metaphyseal chondrodysplasia type Schmid but not several other forms of metaphyseal chondrodysplasia. J Med Genet 1996, in press.
24.
Chan D, Cole WG, Rogers JG, Batsman JF: Type X collagen multirner assembly in vitro is prevented by a gly618 to val mutation in the 0~l(X) NCl domain resulting in Schrnid rnetaphyseal chondrodysplasia. J Biol Chem 1995, 270:4558-4562.
9. •
10. ••
Vikkula M, Madman ECM, Lui VCH, Zhidkova NI, Tiller GE, Goldring MB, Van Beersum SEC, De Waal Malefijt MC, Van den Hoogen FHJ, Ropers HH: Autosornal dominant and recessive
Muenke M: Finding genes involved in human developmental disorders. Curr Opin Genet Dev 1995, 5:354-361. annotation [14°°].
Bone dysplasias in man Franc•man•, Mclntosh and Wilkin
25.
Rosati R, Horan GSB, Pinero GJ, Garofalo S, Keene DR, Horton WA, Vuorio E, De Crombrugghe B, Behringer RR: Normal long bone growth and development in type X collagen-null mice. Nat Genet 1994 8:129-135.
26. *,,
Spranger J, Winterpacht A, Zabel B: The type II collagenopathies: a spectrum of chondrodysplasias. Eur J PedJatr 1994, 153:56-65. The most recent review of type II collagen phenotypes, describing both radiographic and molecular features of these disorders. This was the first review to analyze the relationship between genotype and phenotype in the type II collagenopathies. 2?
28.
29.
30.
Stickler GB, Belau PG, Farrell FJ, Jones JD, Pugh DG, Steinberg AG, Ward LE: Hereditary progressive arthro-ophthalmopathy. Mayo Cfin Proc 1965, 40:433-455. Ahmad NN, Ala-Kokko L, Knowlton RG, Jimenez SA, Weaver El, Maguire JI, Tasman W, Prockop DJ: Stop codon in the procollagen II gene (COL2A1) in a family with the Stickler syndrome (arthro-ophthalmopathy). Proc Natl Acad Sci USA 1991,88:6624-6627. Ahmad NN, McDonald-McGinn DM, Zackai EH, Knowlton RG, LaRossa D, DiMascio J, Prockop DJ: A second mutation in the type II procollagen gene (COL2A1) causing Stickler syndrome is also a premature termination ¢odon. Am J Hum Genet 1993, 52:39-45. RitvaniemiP, Hyland J, Ignatius J, Kivirikko KI, Prockop DJ, Ala-Kokko L: A fourth example suggests that premature termination codons in the COL2AI gene are a common cause of the Stickler syndrome: analysis of the COL2A1 gene by denaturing gradient gel electrophoresis. Genomics 1993, 17:218-221.
31.
Brown D M, Nichols BE, Weingeist TA, Sheffield VC, Kimura AE, Stone EM: Procollagen II gene mutation in Stickler syndrome. Arch Ophthalmol 1992, 110:1589-1593.
32.
Brown DM, Vandenburgh K, Kimura AE, Weingeist TA, Sheffield VC, Stone EM: Novel frameshift mutations in the procollagen 2 gene (COL2A1) associated with Stickler syndrome (hereditary arthro-ophthalmopathy). Hum Mol Genet 1995, 4:141-142.
33.
Knowlton RG, Weaver El, Struyk AF, Knobloch WH, King RA, Norris K, Shamban A, Uitto J, Jimenez SA, Prockop DJ: Genetic linkage analysis of hereditary arthro-ophthalmopathy (Stickler syndrome) and the type II procollagen gene. Am J Hum Genet
34.
Vintiner GM, Temple K, Middleton-Price HR, Baraitser M, Malcolm S: Genetic and clinical heterogeneity of Stickler syndrome. Am J Med Genet 1991,41:44-48.
35.
Bonaventure J, Philippe C, Plessis G, Vigneron J, Lasselin C, Maroteaux P, Gilgenkrantz S: Linkage study in a large pedigree with Stickler syndrome: exclusion of COL2A1 as the mutant gene. Hum Genet 1992, 90:164-158.
1989, 45:581-688.
36. **
Brunner HG, Van Beersum SEC, Warman ML, Olsen BR, Ropers HH, Mariman ECM: A Stickler syndrome gene is linked to chromosome 6 near the COL11A2 gene. Hum Mol Genet 1994, 3:1 561-1564. Describes linkage of Stickler syndrome in a large Dutch family to a region of chromosome 6 containing one of the genes for type Xl collagen. This established the map location of a second Stickler syndrome locus and paved the way for the identification of the mutation (see [10"°]). 37 •
Snead MP, Payne SJ, Barton DE, Yates JRW, Al-lmara L, Pope FM, Scott JD: Stickler syndrome: correlation between vitro-retinal phenotypes and linkage to Col2A1. Eye 1994, 8:609-614. This paper discusses the relationship between Stickler syndrome families linked to COL2A 1 and those not linked to COL2A 1. The authors suggest that the early onset high myopia found in the majority of Stickler families is found only in families linked (or with genetics consistent with linkage) to COL2A 1.
38.
Mayne R, Brewton RG, Mayne PM, Baker JR: Isolation and characterization of the chains of type V/typeXl collagen present in bovine vitreous. J Biol Chem 1993, 268:9381-9386.
39. •
Bogaert R, Wilkin D, Wilcox WR, Lachman R, Rimoin DL, Cohn DH, Eyre DR: Expression in cartilage of a 7-amino acid deletion in type II collagen from two unrelated individuals with Kniest dysplasia. Am J Hum Genet 1994, 55:1128-1136. See annotation [40"]. 40. •
Wilkin DJ, Bogaert R, Lachman R, Rimoin DL, Eyre DR, Cohn DH: Single amino acid substitutions (glycine 103 to aspartate) in the type II collagen triple helix can produce Kniest dysplasia. Hum Mol Genet 1994, 3:1999-2003.
307
Together with [39*], this paper describes additional COL2A1 mutations in patients with Kniest dysplasia. These authors present a complete radiographical, histological, biochemical, and molecular description of the cases analyzed. They present the first and, to date, only known instance of a Kniest individual arising from a non deletion/exon-skip mutation. 41.
Winterpacht A, Schwarze U, Mundlos S, Menger H, Spranger J, Zabel B: Alternative splicing as the result of a type II procollagen gene (COL2A1) mutation in a patient with Kniest dysplasia. Hum Mo/Genet 1994, 3:1891-1893.
42.
H~stbacka J, Kaitila I, Sistonen P, De la Chapelle A: Diastrophic dysplasia gene maps to the distal long arm of chromosome 5. Proc Nat Acad Sci USA 1990, 87:8056-8059.
43.
Superti-Furga A: A defect in the metabolic activation of sulfate in a patient with achondrogenesis type lB. Am J Hum Genet 1994, 55:1137-1145.
44.
Stanescu R, Stanescu V, Muriel MP, Maroteaux P: Multiple epiphyseal dy:,plasia, Fairbank type: morphologic and biochemical study of cartilage. Am J Med Genet 1993, 45:501-507.
45.
Hedbom, E, Antonsson P, Hjerpe A, Aeschlimann D, Paulsson M, Rosa-Pimentel E, Sommarin Y, Wendel M, Oldberg A, Heinegard D: Cartilage matrix proteins. An acidic oligomeric protein (COMP) detected only in cartilage. J Bio/Chem 1992, 267:6132-6136.
46.
Newton G, Weremowicz S, Morton CC, Copeland NG, Gilbert DJ, Jenkins NA, Lawler J: Characterization of human and mouse cartilage oligomeric matrix protein. Genomics 1994, 24:435-439.
47.
Briggs MD, Rasmussen IM, Weber JL, Yuen J, Reinker K, Garber AP, Rim•in DL, Cohn DH: Genetic linkage of mild pseudoachondroplasia (PSACH) to markers in the pericentri¢ region of chromosome 19. Genomics 1993, t 8:656-660.
48.
Hecht JT, Franc•man• CA, Briggs MD, Deere M, Conner B, Horton WA, Warman M, Cohn DH, Blanton SH: Linkage of typical pseudoachondroplasia to chromosome 19. Genomics 1993, 18:661-666.
49. •
Oehlman R, Summerville GP, Yeh G, Weaver El, Jimenez SA, Knowlton RG: Genetic linkage mapping of multiple epiphyseal dysplasia to the pericentromeric region of chromosome 19. Am J Hum Genet 1994, 54:3-10. Together with [47] and [48], this paper maps PSACH and MED to chromosome 19. When the cartilage protein COMP was mapped to the same region on chromosome 19, this led to the identification of specific mutations that result in the disease phenotype (see [1"°] and [2°°]). 50.
LoughlinJ, Irven C, Mustafa Z, Briggs MD, Carr A, Lynch SA, Knowlton RG, Cohn DH, Sykes B: Identification of five novel mutations in the cartilage oligomatrix protein gene in pseudoachondroplasia and multiple epiphyseal dysplasia. Hum Mutat 1996, in press.
51. •
Briggs MD, Choi H, Warman ML, Loughlin JA, Wordsworth P, Sykes BC, Irven CMM, Smith M, Wynne-Davies R, Lipson MH et aL: Genetic mapping of a locus for multiple epiphyseal dysplasia (EDM2) to a region of chromosome 1 containing a type IX collagen gene. Am J Hum Genet 1994, 55:678-684. Describes the linkage of a form of MED to a region containing COLgA2obviously a very good candidate gene for this phenotype-leading to the confirmation of the gene by the identification of the mutation in [52"°]. 52. **
MuragakiY, Mariman ECM, Van Beersum SEC, Perala M, Van Mourik JBA, Warman ML, Olsen BR, Hamel BCJ: A mutation in the gene encoding the alpha-2 chain of the fibril-associated collagen IX, COLgA2, causes multiple epiphyseal dysplasia (EDM2). Nat Genet 1996, 12:103-105. First identification of a mutation in a type IX collagen gene, gaining insight into how mutations in this protein, which is tightly associated with collagen types II and XI, can lead to specific phenotypes. 53. ••
Franc• B, Meroni G, Parenti G, Levilliers J, Bernard L, Gebbia M, Cox L, Maroteaux P, Sheffield L, Rappold GA et aL: A cluster of sulfatase genes on Xp22.3: mutations in chondrodysplasia punctata (CDPX) and implications for Warfarin embryopathy. Cell 1995, 81:15-25. The authors describe the identification of three genes with homology to the sulfatase family of genes in Xp22.3, the region where the CDPX gene has been assigned. Point mutations have been identified in one of the genes, arylsulfatase E, in five patients with CDPX. 54.
Loughlin J, Irven C, Hardwick U, Butcher S, Walsh S, Wordsworth P, Sykes B: Linkage of the gene that encodes the alpha-1
308
Genetics of disease
chain of type V collagen (COLSA1) to type II Ehlers-Danlos syndrome (EDSII). Hum Mo/Genet 1gg5, 4:1649-1651. 55. •-
Foster JW, Dominguez-Steglich MA, Guioli S, Kwok C, Waller PA, Stevanovic M, Weissenbach J, Mansour S, Young ID, Goodfellow PN et al.: Campomelic dysplasia and autosomal sex reversal caused by mutations in an SRY-related gene. Nature t 994, 372:525-530. In this innovative paper, the authors describe the cloning of a transtocation chromosome breakpoint from a sex-reversed patient with campomelic dysplasia, resulting in the recognition of SOX9, a SRY-related gene, as the cause of this condition.
56. •e
ThomasJT, Lin K, Nandedkar M, Camargo M, Cervenka J, Luyten FP: A human chondrodysplasia due to a mutation in a TGF-13 superfamily member. Nat Genet 1996, 12:315-317. The authors describe a mutation in CDMP-1, a cartilage derived morphogenetic protein closely related to the subfamily of bone morphogenetic proteins, in a family with the recessive acromesomelic chondrodysplasia, Hunter-Thompson type. 5Z
Nicholls AC, McCarron S, Narcisi P, Pope FM: Molecular abnormalities of type V collagen in Ehlers-Danlos syndrome. Am J Hum Genet 1994, 55:A233.
Bone dysplasias in man: molecular insights Clair A Francomano*, lain Mclntosht and Douglas J Wilkin$ The recent explosion in the number of identified genes involved in the human skeletal dysplasias has dramatically advanced this particular field. While linkage efforts are mapping hereditary disorders of the skeleton at an ever accelerating pace, progress in the Human Genome Project is providing tools for rapid gene discovery after the map location is known. Emerging themes in the molecular analysis of the skeletal dysplasias include the identification of allelic series of disorders and the existence of mutational and genetic heterogeneity in many of these conditions. Allelic series include those conditions caused by mutations in the genes encoding type II collagen (CQL2A1), cartilage oligomeric matrix protein (COMP),fibroblast growth factor receptor 3 (FGFRJ) and the diastrophic dysplasia sulfate transporter (DTDST). The recognition of these phenomena has initiated the analysis of the relationship between disease phenotype and gene.
Addresses
*$Medical Genetics Branch, National Center for Human Genome Research, National Institutes of Health, Bethesda, Maryland 20892,
USA *e-mail: [email protected] ~e-mail: Dwilkin@ nchgr.nih.gov tCenter for Medical Genetics, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Block 1012G Baltimore, Maryland 21287, USA; e-mail: [email protected] Current Opinion in Genetics & Development 1996, 6:301-308
© Current Biology Ltd ISSN 0959-437X Abbreviations achondrogenesis type IB ACG IB atelosteogenesis type II AO II
COMP DTD DTDST FGFR MED NC1 NC2 PSACH SED SEMD SMCD
cartilage oligomeric matrix protein diastrophic dysplasia diastrophic dysplasia sulfate transporter fibroblast growth factor receptor multiple epiphyseal dysplasia carboxy-terminal non-collagenous domain amino-terminal non-collagenous domain pseudoachondroplasia spondyloepiphyseal dysplasia spondyloepimetaphyseal dysplasia Schmid metaphyseal chondrodysplasia
Introduction The skeletal dysplasias are a heterogeneous group of disorders that we have only recently begun to understand at the molecular level. Although the clinical delineation of the skeletal dysplasias began in the mid-1960s, and biochemical and molecular analyses of type I collagen in osteogenesis imperfecta were well advanced in the 1980s, little was known about the genes underlying the remaining skeletal dysplasias when the current decade began. Advances in map-based gene discovery have enabled enormous progress in the past 2-3 years. The identification
of specific genes (Table 1), mutations, and (increasingly) genotype-phenotype relationships lend promise to a greater understanding of skeletal development in the years ahead. Specifically, recent advances include the mapping of multiple disorders for which the specific genes have not yet been identified. In addition, a number of disease-linked genes have been identified, including those for pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (MED) [1",2"°], Schmid metaphyseal chondrodysplasia (SMCD) [3], Jansen metaphyseal chondrodysplasia [4"'], diastrophic dysplasia (DTD) [5°°], atelosteogenesis type II (AO II) [6"°], and achondrogenesis type IB (ACG IB) [7°']. The past few years have also witnessed the inclusion of Kniest dysplasia [8] and spondyloepimetaphyseal dysplasia (SEMD) of the Strudwick type [9 °] in the list of type II collagen disorders and the identification of a second gene linked with Stickler syndrome [10 °°] (Table 1). Perhaps the greatest excitement surrounding the recent advances in skeletal dysplasia research has centered around achondroplasia--the most common human skeletal dysplasia--and its related disorders, hypochondroplasia and thanatophoric dysplasia. These conditions--along with the craniosynostosis syndromes that include Pfeiffer syndrome, Apert syndrome, Crouzon syndrome, Crouzon syndrome with Acanthosis-Nigricans [11"*], and JacksonWeiss syndrome--have been shown to be caused by mutations in the fibroblast growth factor receptor (FGFR) gene family. A considerable amount of literature has been published on FGFR mutations in the achondroplasia family of disorders and the craniosynostoses over the past 2 years; we refer the reader to a number of recent reviews [12°°-14°°]. In addition, many reviews have been written on the disorders of collagens types I and II, including osteogenesis imperfecta types I-IV, and the Ehlers-Danlos syndromes and, therefore, these disorders will not be discussed here [15-171. In this review, we concentrate on those genes which have recently been shown to play important roles in skeletogenesis, including those encoding collagen types II, IX, X, and XI, the diastrophic dysplasia sulfate trasnporter, and cartilage oligomatrix protein. Type X c o l l a g e n a n d S c h m i d m e t a p h y s e a l dysplasia
Type X collagen is the product of a condensed gene, COL1OA1, which contains only two introns, and thus is substantially smaller than those genes encoding fibrillar collagens. The first exon is non-coding, the second encodes the signal peptide and part of the amino-terminal non-collagenous domain (NC2), and the third encodes the
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Genetics of disease
Table 1 Disease-linked genes for skeletal dysplasia and related disorders. Gene
Diseases
References
COL 1A I
Osteogenesis imperfecta types I-IV, and Ehlers-Danlos syndrome type VII
[15] [17]
COL 1A2
Osteogenesis Imperfecta types I-IV, and Ehlers-Danlos syndrome type VII
[15] [17]
COL3A 1
Ehlers-Danlos syndrome type IV
[16]
COL5A 1
Ehlers-Danlos syndrome type II
[54,5?]
COL2A 1
Achondrogenesis type II, hypochondroplasia, Kniest dysplasia, Spondyloepi(meta)physeal dysplasia, Stickler syndrome and osteoarthritis with mild SED
[26"] [26"'] [8,26"] [9",26 "°] [26"] [26 "°]
COL9A2
Multiple epiphyseal dysplasia
COLIOA1
Schmid metaphyseal chondrodysplasia
[3]
COL11A2
Stickler syndrome and OSMED
[10"] [10"]
COMP
Pseudoachondroplasia and multiple epiphyseal dysplasia
[1 "*,2"*] [2"]
DTDST
Diastrophic dysplasia, atelosteogenesis type II and achondrogenesis type IB
[5"'] [6"] [7"]
PTH-PTHrP receptor
Jansen metaphyseal chondrodysplasia
[4"]
SOX9
Campomelic dysplasia
[55"]
Arylsulfatase E
Chondrodysplasia punctata
[53"']
CDMP- 1
Acromesomelic chondrodysplasia (Hunter-Thompson type)
[56"]
[53"]
Achondroplasia, Thanatophoric dysplasia (types 1 and 2), Hypochondroplasia and Crouzon syndrome with Acanthosis-Nigricans
[12"-14"]
FGFR2
Crouzon syndrome, Apert syndrome, Jackson-Weiss syndrome and Pfeiffer syndrome
[12"-14"] [12"-14"*] [12"-14"] [12"-14"]
FGFR1
Pfeiffer syndrome
[12--14 °°]
FGFR3
[12"-14"] [12"-14"*] [11 "]
remainder of NC2, the entire collagenous domain and the carboxy-terminal non-collagenous domain, NC1 [18]. COLIOA1 has been implicated in the etiology of Schmid metaphyseal chondrodysplasia (SMCD), a rare autosomal dominant disorder causing short stature; abnormal distal tibial metaphyses with anterior cupping and splaying and
sclerosis of the ribs arc considered diagnostic of this disease. As in other metaphyseal dysplasias, growth plate histology shows dense collagen surrounding clusters of hypertrophic cells extending into the metaphyses [19]. In a large Mormon kindred with SMCD, Watman eta/. [3] have found a 13bp deletion in the NC1 domain of COLIOA1 segregating with the disorder. Over 20 additional mutations have been identified in the COLIOA1 genes of SMCD patients, each within the NC1 domain [20*-22",231. Approximately half the mutations are single amino acid substitutions, and the remainder are frameshift or nonsense mutations, leading to premature termination of the polypeptide (although equimolar amounts of the normal and mutant transcript, and probably protein monomers, are expected as these premature termination codQns are in the terminal exon). It has been suggested that the mutant polypeptides are unable to participate in trimer formation as trimerization is initiated at the carboxy-terminal end of the protein. The relatively mild SMCD phenotype could be due to the reduction in the amount of normal type X collagen deposited in the exttacellular matrix. This hypothesis is supported by in vitro expression studies in which type X collagen carrying a SMCD mutation neither self-assembled nor interacted with normal monomeric polypeptides [241. An alternative mechanism is that SMCD is the resuh of a dominant negative effect of the mutant polypeptide on normal function. This hypothesis is supported by the observation that mice whose endogenous Co/l&ll genes are inactivated do not have any demonstrable abnormal phenotype up to 3 months of age, in either the heterozygous or homozygous state [25]. Given the presumed role of type X collagen in endochondral ossification, a normal phenotype in the absence of the protein is surprising. It should be noted, however, that the lack of a phenotype in these Co/l&d-null mice may be the result of species-specific differenccs in type X collagen function or anatomical differences that allow mice to compensate for the absence of the protein. Furthermore, the concentration of mutations within the NCI domain cannot be taken as supporting a haplo-inst, fficiency model as the level of COLIOA1 transcript could be redticed by mutations elsewhere in the gene; such mutations have not been identified, despite the efforts of many investigators. This point is reviewed extensively by Wallis eta/. [23]. T y p e II c o l l a g e n d i s o r d e r s a n d r e l a t e d diseases The type II collagen disorders are a phenotypically heterogeneous group of conditions which affect predominantly the skeletal and visual systems (see Fig. 1). Known type II collagen disorders include achondrogenesis type II, hypochondrogenesis, Kniest dysplasia, a number of types of spondyloepiphyscal dysplasia (SED), SEMD, Stickler syndrome, and osteoarthritis with mild SED [26°']. Recent significant findings in this area include the confirmation of genetic heterogeneity in Stickler syndrome by the
Bone dysplasiasin man Francomano, Mclntosh
and Wilkin
303
facies, progressive myopia and cleft palate [27]. A number of COL2A1 mutations have been identified in individuals with Stickler syndrome and, interestingly, all except one result in premature termination codons [28-32].
identification of a second Stickler syndrome gene and the inclusion of Kniest dysplasia in this list of disorders.
Stickler syndrome Stickler syndrome is one of the milder type II collagen disorders. As is the case in many autosomal dominant disorders, the phenotype is variable. Affected individuals may exhibit mild spondyloepiphyseal dysplasia, premature osteoarthritis, joint hypermobility, hearing loss, a specific
Genetic heterogeneity has been reported for this disorder on the basis of linkage observations [33-35]. Type II collagen is closely associated with both type IX collagen and type XI collagen in cartilage collagen fibrils in
Figure 1 Type II collagendisorders G 574-'-S
G691~R
G817-*V
G943~S
Disorder AII-H
5' i
R?5-*C
G175--'R
~ SED
R 519~C
256-73
G853--'E G910--*C 604-621
964-99
R
5' i
875-?* G274~S G154--,R
SEMD
G 709--,C
G997~S
5' I
I
G304-*C
91-108~4-41 5' I
U
102-8
Stickler
97O-84*
R789-~C
G292-*V
G103--*D
Kniest
I
U
2~6 -73
~
G841--~S
36~78
1007-12
NI
U
142-56 274-9 223-55
5' Q Q
Q
Q
QI
'~ 1996 Current Opinion in Genetics & Development
Substitution
Deletion
Duplication
Stop codon
O A schematic diagram illustrating the location of COL2A1 mutations that lead to collagen II disorders: achondrogenesis type II-hypochondrogenesis (All-H), spondyloepiphyseal dysplasia (SED), spondyloepimetaphyseal dysplasia (SEMD), Kniest dysplasia and Stickler syndrome. The COL2A 1 gene is represented by a horizontal light-shaded bar. Mutations resulting in amino acid substitutions (open arrows), deletions (darker shaded boxes), duplications (asterisks), and stop codons (hexagons) are shown. The residue numbers of the mutated bases in the collagen triple helix are indicated. As the recognition of COL2A1 mutations is a rapidly evolving process, the authors have not attempted to include all known mutations. (Original figure courtesy of Daniel Cohn and Geert Mortier.)
304 Geneticsof disease
the extracellular matrix. This k n o w l e d g e - - t o g e t h e r with information on the chondrodysplasia mouse (see review by S Darling, ths issue [pp 289-294])--prompted Brunner et al. [36 °°] to examine genes encoding collagen types IX and XI in Stickler syndrome families in which the phenotype was not linked to COL2A1. T h e y found linkage of the Stickler syndrome phenotype to 6p22-p21.3, the region where C O L l l A 2 maps, in a large Dutch family. Subsequently, Vikkula et al. [10"*] have found a C O L l l A 2 exon skip mutation in this family. Interestingly, disease-affected individuals in this Stickler syndrome family lack the significant ocular deformities characterisitic of the disease, which are present in the majority of affected persons from families linked to COL2A1 [37*]. This may be explained by the fact that in the eye vitreous fluid, the product of the C O L l l A 2 gene is replaced in the collagen XI fiber by the product of the COL5A2 gene [38].
Otospondylomegaepiphyseal dysplasia syndrome In their study, Vikkula et al. [10 "°] also found a C O L l l A 2 mutation in a family with otospondylomegaepiphyseal dysplasia syndrome, an autosomal recessive disorder characterized by spondyloepiphyseal dysplasia and sensorineural hearing loss. Affected children in this family were homozygous for the mutation, a G--~A transition, resulting in a Gly-+Arg amino acid substitution in the triple helical domain of the protein, whereas unaffected children were heterozygous for the mutation.
Kniest dysplasia In a family that proved to be highly instructive, a woman with Stickler syndrome had a daughter with Kniest dysplasia, a much more severe skeletal dysplasia with extreme short stature and profound joint involvement [8]. T h e mutation was a 28 bp deletion spanning the COL2A1 exon 12-intron 12 junction, resulting in the skipping of exon 12. T h e mother was found to be a somatic mosaic for this m u t a t i o n - - t h e first Stickler COL2A1 mutation that is not a premature termination codon. Moreover, this was the first mutation identified in an individual with Kniest dysplasia and added the phenotype to the growing list of type II collagen disorders. Additional COL2A1 mutations have been identified recently in individuals with Kniest dysplasia ([39*,40",41]; DJ Wilkin et a/., Am J Hum Genet 1993, $3:A210; GR Mortier et al., Am J Hum Genet 1995, 87:A221). All of these mutations, except for one, are either small deletions or result in exon skipping in type II collagens; one mutation found in two unrelated individuals resulted in a deletion of seven amino acids encoded by exon 12 [39"]. T h e exception is a Glyl03-+Asp substitution, resulting in the substitution of a glycine residue encoded by exon 12, which is deleted in three other individuals with Kniest dysplasia [40*]. Mutational patterns seem to be emerging in some of the type II collagen phenotypes, s u c h as premature termination codons resulting in Stickler syndrome and small deletions around exon 12 resulting predominantly in Kniest
dysplasia. Further delineation on the genotype-phenotype relationships will await the recognition of additional mutations.
The dystrophic dysplasia sulfate transporter disorders D T D , AO II, and ACG IB are all severe autosomal recessive skeletal dysplasias that have recently been found to result from mutations in the diastrophic dysplasia sulfate transporter (DTDST) gene [5**-7 °'] demonstrating another allclic series of disorders resulting from mutations in a single gene.
Diastrophic dysplasia D T D is recognized at birth by a severe club foot deformity and an abducted 'hitchhiker' thumb. Patients also have profound short-limbed dwarfism, joint dysplasia, and kyphoscoliosis (deformation of the spine). Malformed pinnae of the ear with calcification of the cartilage is another characteristic of this disease. H~stbacka et al. [42] stated that 160 patients with D T D have been diagnosed in Finland, suggesting a founder effect. In a separate study, H~stbacka and her colleagues [5"'] have used this superb source of related families with D T D for the positional cloning of the D T D gene by fine structure linkage disequilibrium mapping. The gene was found to encode a novel sulfate transporter. Impaired function of this transporter would be expected to lead to the undersulfation of proteoglycans in the cartilage extracellular matrix, resulting in the disease phenotype. Although the single mutation responsible for the great majority of D T D alleles found in affected Finnish individuals has not yet been found, point mutations have been localized in non-Finnish patients [5*']. One mutation, a single-base deletion in codon 575, creatcs a frameshift and premature termination codon after nine codons which would eliminate 20% of the encoded protein. Three D T D patients from the Netherlands, France, and Germany were found to carry this particular mutation.
Atelosteogenesis type II AO II--charactcrized by severely shortened limbs, small chest, scoliosis, club foot, abducted thumbs and great toes, and cleft p a l a t e - - i s lethal in the newborn period. Histologically, cartilage collagen in incidences of AO II, is clumped and deficient--similar to the cartilage appearance in D T D . As a result of the clinical and histological similarities between AO II and D T D , a shared pathogenesis involving the same biochemical pathway and possibly the same gene was postulated. T h e identification of the D T D S T gene allowed investigation of the hypothesis that these diseases are related genetically. Cultured skin fibroblasts from three patients with AO II have been found to be defective in sulfate transport and sulfation of proteoglycans [6"']. Five D T D S T mutations, accounting for the six AO II alleles in these
Bone dysplasiasin man Francomano,Mclntoshand Wilkin 305
patients, were identified. One of these mutations, found in two unrelated AO II probands as a single base pair deletion (-adenosine, nucleotide 1751), has also been identified in three unrelated D T D patients and one ACG IB patient. T h e other mutation in one of the AO II patients was a C--+T transition at nucleotide 862, resulting in an Arg279--)Trp amino acid substitution. This mutation was also found in four D T D chromosomes. T h e AO II mutations are in the coding regions of the protein, resulting in late frameshift or missense mutations [7°°].
hands and scoliosis (lateral deformation of the spine); radiographically, metaphyseal and epiphyseal abnormalities of the hands and long bones and anterior beaking of the vertebrae are also apparent. M E D is characterized by abnormalities in the epiphyseal centers of the knees, hands, shoulders, and hips. Radiographical and histological similarities between these two conditions led to the hypothesis that they are part of the same bone dysplasia family [44] and are perhaps the result of mutations in the same gene.
Achondrogenesis IB ACG IB of the Parenti-Fraccaro type is an autosomal recessive disorder in which affected individuals are either stillborn or die within minutes of birth, and it is the most severe of these three D T D S T gene disorders. Superti-Furga [43] found a reduced amount of proteoglycans in cartilage of patients with ACG lB. He further demonstrated that these proteoglycans were synthesized normally but were not sulfated and suggested that such a finding could be explained by deficent activity of one of the enzymes responsible for the biological activity of sulfate. Recently, Superti-Furga et al. [7°°] have identified additional sulfate defects in ACG IB probands and found six different mutations in the D T D S T gene from 11 of 12 ACG IB alleles, with one of the mutations (-adenosine, nucleotide 1751) previously identified in D T D and AO II patients. Of the ACG IB probands studied to date, all have mutations in the coding regions of both strands, with most leading to premature termination codons [6",7°°].
Cartilage oligomeric matrix protein ( C O M P ) - - a member of the thrombospondin family of extracellular calcium binding p r o t e i n s - - i s a pentameric glycoprotein of the cartilage extracellular matrix found in the territorial matrix surrounding chondrocytes [45]. T h e human COMP gene has recently been mapped to chromosome 19p13.1 [46]. Linkage studies have placed PSACH [47,48] and M E D [49 °] in the same chromosomal region, making the COMP gene an ideal candidate to screen for mutations in these two disorders. Recently, Hecht et al. [1"*] and Briggs et al. [2"°1 have reported mutations in the COMP gene in individuals with PSACH. Hecht etal. [1 °°] identified a loss of a conserved aspartate residue from a calmodulin-like repeat encoded by cxon 13B in five unrelated patients with PSACH (as well as three other mutations) and Briggs etal. [2"'] found a three base pair deletion in exon 10 of the COMP gene, which eliminated an aspartic acid codon from the fourth calmodulin-like repeat of COME Cohn and colleagues [2"*,50] have also identified additional exon 10, exon 11, and exon 13 mutations in PSACH patients, and exon 10 and exon 11 mutations in M E D (Fairbanks type) sporadic patients and families--confirming the allclic relationship between these related phenotypes .
These new findings once again define a family of diseases which results from defects in a single gene. It has been proposed that the differences in severity of these three phenotypes results from amount of residual D T D S T protein activity present, with ACG IB representing the null phenotypc with complete loss of function, AO II representing a partial loss of function, and D T D representing an even milder loss of function [6"']. This theory is supported by the findings that no D T D probands have two mutations in the coding region of DTDST, whereas the AO II mutations are in the coding regions of the protein--resulting in late frameshift or missense m u t a t i o n s - - a n d the ACG IB probands always have mutations in the coding regions of both alleles, with most leading to premature termination codons [5*°-7"°]. Identification of the Finnish mutation, which accounts for such a great number of D T D probands, will aid in the explication of the relationship between phenotype and mutation type in this family of disorders.
Cartilage o l i g o m e d c matrix protein and type I X collagen PSACH and M E D are autosomal dominant forms of short-limbed dwarfism. PSACH is characterized by short stature, which is recognized in early childhood, short
In families where the M E D phenotype was not linked to COME Briggs et al. [51"] demonstrated linkage of the phenotype to the region of chromosome 1 containing COLgA2, which encodes the ~-2 chain of the type IX collagen. This observation confirmed genetic heterogeneity in MED. More recently, Muragaski et al. [52"*] have found a COLgA2 splice site mutation resulting in exon skipping in a Dutch family with MED, thus confirming both the genetic heterogeneity of the disorder and a role for COLgA2 in the cause of MED.
Conclusions Recent findings in the studies of skeletal dysplasias have, as a common theme, the existence of allelic series with related disorders resulting from distinct mutations in the same gene. This phenomenon has been described for the genes encoding the FGFRs, type I collagen, type II collagen, type XI collagen, D T D S T , and COME T h e identification of novel components of the extracellular matrix will lead to the identification of additional disease genes, and eventually the understanding of how these components interact with each other during both normal and aberrant skeletogenesis.
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References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as: • ••
of special interest of outstanding interest
1. ••
Hecht JT, Nelson LD, Crowder E, Wang Y, Elder FFB, Harrison WR, Francomano CA, Prange CK, Lennon GG, Deere M, Lawler J: Mutations in exon 17B of cartilage oligomeric matrix protein (COMP) cause pseudoachondroplasia. Nat Genet 1995, 10:325-329. This paper (and [2°°]) describes the first COMP mutations found in PSACH. Using the candidate gene approach, the authors identified mutations in eight familial and isolated PSACH cases, all in exon 1 ?B (corresponding to exon 13 of [2°°]). Six of the mutations delete or change a well- conserved aspartic acid residue within the calcium binding repeats. 2. ••
Briggs MD, Hoffman SMG, King LM, Olsen AS, Mohrenweiser H, Leroy JG, Mortier GR, Rimoin DL, Lachman RS, Gaines ES et al.: Pseudoachondroplasia and multiple epiphyseal dysplasia due to mutations in the cartilage ollgorneric matrix protein gene. Nat Genet 1995, 10:330-336. This paper (and [1°°]) describes the first COMP mutations identified in PSACH, as well as the first MED mutations in COMP, demonstrating that PSACH and some forms of MED are allelic. The mutations identified, as with those described in [1°°], are in the calcium binding domain. 3.
Warman ML, Abbott M, Apte SS, Hefferon TW, Mclntosh I, Cohn DH, Hecht JT, Olsen BR, Francomano CA: A mutation in the human type X collagen gene in a family with Schmid rnetaphyseal chondrodysplasia. Nat Genet 1993, 5:?9-82.
Schipani E, Krusw K, J~ippner H: A constitutively active mutant PTH-PTHrP receptor in Jansen-type metaphyseal chondrodysplasia. Science 1995, 268:98-100. The authors describe a mutation in the parathyroid hormone-parathyroid hormone-related peptide receptor in a patient with Jansen-type metaphyseal dysplasia. The authors suggest that their findings explain the abnormal formation of endochondral bone in this rare short-limbed dwarfism.
osteochondrodysplaslas associated with the COL11A2 locus. Cell 1995, 80:431-437 This paper identifies COL 11A2 mutations in a Stickler syndrome (dominant) family and OSMED (recessive) family. These are the first two phenotypes found to result from mutations in type XI collagen. The observations reported here establish COL11A2 as a second locus causing Stickler syndrome. The authors propose a molecular mechanism for differences in the ocular phenotype between Stickler syndrome caused by COL2A1 mutations, and those caused by COL11A2. 11. **
Meyers GA, Orlow SJ, Munro IR, Przylepa KA, Jabs EW: Fibroblast growth receptor 3 (FGFR3) transrnembrane mutation in Crouzon syndrome with acanthosis nigricans. Nat Genet 1995, 11:462-464. The authors identify mutations in FGFR3 in a disease outside the aehondroplasia spectrum (including thanatophoric dysplasia and hypochondroplasia), demonstrating locus heterogeneity in Crouzon syndrome and expanding the phenotypic spectrum resulting from mutations in FGFR3. 12. See 13. **
Park V~J, Bellus GA, Jabs EW: Mutations in fibroblast growth factor receptors: phenotypic consequences during eukaryotic development. Am J Hum Genet 1995, 57:748-745. See annotation [14°']. 14. Winter RM: Recent molecular advances in dysrnorphology. eo Hum Mol Genet 1995, 4:1699-1 ?04. Together with [12 °°] and [13°°], this review provides an excellent description of recent findings of human developmental disorders, including phenotypes resulting from mutations in the FGFRs. 15.
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5. ••
H~stbacka J, De la Chapetle A, Mahtani MM, Clines G, ReeveDaly MP, Daly M, Hamilton BA, Kusumi K, Trivedi B, Weaver A et aL: The diastrophic dysplasia gene encodes a novel sulfate transporter: positional cloning by fine-structure linkage disequilibrium mapping. Ceil 1994, 78:1073-108'7. A fascinating paper describing the identification of a novel sulfate transporter gene and the identification of mutations in this gene in individuals with DTD. The authors use linkage disequilibrium mapping to identify the gene, capitalizing on the high carrier frequency in the Finnish population. 6. ••
H&stbacka J, Superti-Furga A, Wilcox WR, Rimoin DL, Cohn DH, Lander ES: Atelosteogenesis type II is caused by mutations in the diastrophic dysplasia sulfate-transporter gene (DTDST): evidence for a phenotypic series involving three chondrodysplasias. Am J Hum Genet 1996, 58:255-262. The authors identify the first mutations in AO II, also in the DTDST gene, adding this phenotype to the list of diseases that result from DTDST mutations. 7. ••
Superti-Furga A, Hastbacka J, Wilcox WR, Cohn DH, Van der Harten HJ, Rossi A, Blau N, Rimoin DL, Steinman B, Lander ES, Gitzelmann R: Achrondrogenesis type IB is caused by mutations in the diastrophic dysplasia sulphate transporter gene. Nat Genet 1996, 12:100-102. This paper completes (to date) the list of phenotypes caused by mutations in the DTDSTgene. ACG IB is the most severe of the three disorders due to DTDST mutations and extends the phenotypic spectrum of disease at this locus. 8.
Winterpacht A, Hilbert M, Schwarze U, Mundlos S, Spranger J, Zabel BU: Kniest and Stickler dysplasia phenotypes caused by collagen type II gene (COL2AI) defect. Nat Genet 1993, 3:323-326.
Tiller GT, Polumbo PA, Weis MA, Bogaert R, Lachman RS, Cohn DH, Rimoin DL, Eyre DR: Dominant mutations in the type II collagen gene, COL2A1, produce spondyloepirnetaphyseal dysplasia, Strudwick type. Nat Genet 1995, 11:87-89. This paper identifies COL2A 1 mutations in the Strudwick type of SEMD and adds this phenotype to the list of type II collagen disorders. This phenotype includes dappled metaphyses, which are not seen in SED.
20. •
Mclntosh I, Abbot MH, Warrnan ML, Olsen BR, Francomano CA: Additional mutations of type X collagen confirm COLIOA1 as the Schmid metaphyseal chondrodysplasia locus. Hum Mol Genet 1994, 3:303-307. See annotation [22*]. 21. •
Wallis GA, Rash B, Sweetman WA, Thomas JT, Super M, Evans G, Grant ME, Boot-Handford RP: Amino acid substitutions of conserved residues in the carboxy-terminal domain of the alpha-I(X) chain of type X collagen occur in two unrelated families with rnetaphyseal dysplasia type Schrnid. Am J Hum Genet 1994, 54:169-178. See annotation [22°]. 22. •
Mclntosh I, Abbot MH, Francomano CA: Concentration of mutations causing Schmid metaphyseal chondrodysplasia in the C-terrninal noncollagenous domain of type X collagen. Hum Mutat 1995, 5:121-125. Here we identified additional COLIOA1 mutations which result in the Schmid phenotype. Along with those described in [20",21"], all of the mutations are in the NO1 domain of the protein, suggesting that the mutant chains cannot participate in chain association and trimer formation. 23.
Wallis GA, Rash B, Sykes B, Bonaventure J, Maroteaux P, Zabel B, Wynne-Davis R, Grant ME, Boot-Handford RP: Mutations within the gene encoding the ~l(X) chain of type X collagen (COLIOA1) cause metaphyseal chondrodysplasia type Schmid but not several other forms of metaphyseal chondrodysplasia. J Med Genet 1996, in press.
24.
Chan D, Cole WG, Rogers JG, Batsman JF: Type X collagen multirner assembly in vitro is prevented by a gly618 to val mutation in the 0~l(X) NCl domain resulting in Schrnid rnetaphyseal chondrodysplasia. J Biol Chem 1995, 270:4558-4562.
9. •
10. ••
Vikkula M, Madman ECM, Lui VCH, Zhidkova NI, Tiller GE, Goldring MB, Van Beersum SEC, De Waal Malefijt MC, Van den Hoogen FHJ, Ropers HH: Autosornal dominant and recessive
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26. *,,
Spranger J, Winterpacht A, Zabel B: The type II collagenopathies: a spectrum of chondrodysplasias. Eur J PedJatr 1994, 153:56-65. The most recent review of type II collagen phenotypes, describing both radiographic and molecular features of these disorders. This was the first review to analyze the relationship between genotype and phenotype in the type II collagenopathies. 2?
28.
29.
30.
Stickler GB, Belau PG, Farrell FJ, Jones JD, Pugh DG, Steinberg AG, Ward LE: Hereditary progressive arthro-ophthalmopathy. Mayo Cfin Proc 1965, 40:433-455. Ahmad NN, Ala-Kokko L, Knowlton RG, Jimenez SA, Weaver El, Maguire JI, Tasman W, Prockop DJ: Stop codon in the procollagen II gene (COL2A1) in a family with the Stickler syndrome (arthro-ophthalmopathy). Proc Natl Acad Sci USA 1991,88:6624-6627. Ahmad NN, McDonald-McGinn DM, Zackai EH, Knowlton RG, LaRossa D, DiMascio J, Prockop DJ: A second mutation in the type II procollagen gene (COL2A1) causing Stickler syndrome is also a premature termination ¢odon. Am J Hum Genet 1993, 52:39-45. RitvaniemiP, Hyland J, Ignatius J, Kivirikko KI, Prockop DJ, Ala-Kokko L: A fourth example suggests that premature termination codons in the COL2AI gene are a common cause of the Stickler syndrome: analysis of the COL2A1 gene by denaturing gradient gel electrophoresis. Genomics 1993, 17:218-221.
31.
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33.
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Vintiner GM, Temple K, Middleton-Price HR, Baraitser M, Malcolm S: Genetic and clinical heterogeneity of Stickler syndrome. Am J Med Genet 1991,41:44-48.
35.
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1989, 45:581-688.
36. **
Brunner HG, Van Beersum SEC, Warman ML, Olsen BR, Ropers HH, Mariman ECM: A Stickler syndrome gene is linked to chromosome 6 near the COL11A2 gene. Hum Mol Genet 1994, 3:1 561-1564. Describes linkage of Stickler syndrome in a large Dutch family to a region of chromosome 6 containing one of the genes for type Xl collagen. This established the map location of a second Stickler syndrome locus and paved the way for the identification of the mutation (see [10"°]). 37 •
Snead MP, Payne SJ, Barton DE, Yates JRW, Al-lmara L, Pope FM, Scott JD: Stickler syndrome: correlation between vitro-retinal phenotypes and linkage to Col2A1. Eye 1994, 8:609-614. This paper discusses the relationship between Stickler syndrome families linked to COL2A 1 and those not linked to COL2A 1. The authors suggest that the early onset high myopia found in the majority of Stickler families is found only in families linked (or with genetics consistent with linkage) to COL2A 1.
38.
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39. •
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Wilkin DJ, Bogaert R, Lachman R, Rimoin DL, Eyre DR, Cohn DH: Single amino acid substitutions (glycine 103 to aspartate) in the type II collagen triple helix can produce Kniest dysplasia. Hum Mol Genet 1994, 3:1999-2003.
307
Together with [39*], this paper describes additional COL2A1 mutations in patients with Kniest dysplasia. These authors present a complete radiographical, histological, biochemical, and molecular description of the cases analyzed. They present the first and, to date, only known instance of a Kniest individual arising from a non deletion/exon-skip mutation. 41.
Winterpacht A, Schwarze U, Mundlos S, Menger H, Spranger J, Zabel B: Alternative splicing as the result of a type II procollagen gene (COL2A1) mutation in a patient with Kniest dysplasia. Hum Mo/Genet 1994, 3:1891-1893.
42.
H~stbacka J, Kaitila I, Sistonen P, De la Chapelle A: Diastrophic dysplasia gene maps to the distal long arm of chromosome 5. Proc Nat Acad Sci USA 1990, 87:8056-8059.
43.
Superti-Furga A: A defect in the metabolic activation of sulfate in a patient with achondrogenesis type lB. Am J Hum Genet 1994, 55:1137-1145.
44.
Stanescu R, Stanescu V, Muriel MP, Maroteaux P: Multiple epiphyseal dy:,plasia, Fairbank type: morphologic and biochemical study of cartilage. Am J Med Genet 1993, 45:501-507.
45.
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46.
Newton G, Weremowicz S, Morton CC, Copeland NG, Gilbert DJ, Jenkins NA, Lawler J: Characterization of human and mouse cartilage oligomeric matrix protein. Genomics 1994, 24:435-439.
47.
Briggs MD, Rasmussen IM, Weber JL, Yuen J, Reinker K, Garber AP, Rim•in DL, Cohn DH: Genetic linkage of mild pseudoachondroplasia (PSACH) to markers in the pericentri¢ region of chromosome 19. Genomics 1993, t 8:656-660.
48.
Hecht JT, Franc•man• CA, Briggs MD, Deere M, Conner B, Horton WA, Warman M, Cohn DH, Blanton SH: Linkage of typical pseudoachondroplasia to chromosome 19. Genomics 1993, 18:661-666.
49. •
Oehlman R, Summerville GP, Yeh G, Weaver El, Jimenez SA, Knowlton RG: Genetic linkage mapping of multiple epiphyseal dysplasia to the pericentromeric region of chromosome 19. Am J Hum Genet 1994, 54:3-10. Together with [47] and [48], this paper maps PSACH and MED to chromosome 19. When the cartilage protein COMP was mapped to the same region on chromosome 19, this led to the identification of specific mutations that result in the disease phenotype (see [1"°] and [2°°]). 50.
LoughlinJ, Irven C, Mustafa Z, Briggs MD, Carr A, Lynch SA, Knowlton RG, Cohn DH, Sykes B: Identification of five novel mutations in the cartilage oligomatrix protein gene in pseudoachondroplasia and multiple epiphyseal dysplasia. Hum Mutat 1996, in press.
51. •
Briggs MD, Choi H, Warman ML, Loughlin JA, Wordsworth P, Sykes BC, Irven CMM, Smith M, Wynne-Davies R, Lipson MH et aL: Genetic mapping of a locus for multiple epiphyseal dysplasia (EDM2) to a region of chromosome 1 containing a type IX collagen gene. Am J Hum Genet 1994, 55:678-684. Describes the linkage of a form of MED to a region containing COLgA2obviously a very good candidate gene for this phenotype-leading to the confirmation of the gene by the identification of the mutation in [52"°]. 52. **
MuragakiY, Mariman ECM, Van Beersum SEC, Perala M, Van Mourik JBA, Warman ML, Olsen BR, Hamel BCJ: A mutation in the gene encoding the alpha-2 chain of the fibril-associated collagen IX, COLgA2, causes multiple epiphyseal dysplasia (EDM2). Nat Genet 1996, 12:103-105. First identification of a mutation in a type IX collagen gene, gaining insight into how mutations in this protein, which is tightly associated with collagen types II and XI, can lead to specific phenotypes. 53. ••
Franc• B, Meroni G, Parenti G, Levilliers J, Bernard L, Gebbia M, Cox L, Maroteaux P, Sheffield L, Rappold GA et aL: A cluster of sulfatase genes on Xp22.3: mutations in chondrodysplasia punctata (CDPX) and implications for Warfarin embryopathy. Cell 1995, 81:15-25. The authors describe the identification of three genes with homology to the sulfatase family of genes in Xp22.3, the region where the CDPX gene has been assigned. Point mutations have been identified in one of the genes, arylsulfatase E, in five patients with CDPX. 54.
Loughlin J, Irven C, Hardwick U, Butcher S, Walsh S, Wordsworth P, Sykes B: Linkage of the gene that encodes the alpha-1
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chain of type V collagen (COLSA1) to type II Ehlers-Danlos syndrome (EDSII). Hum Mo/Genet 1gg5, 4:1649-1651. 55. •-
Foster JW, Dominguez-Steglich MA, Guioli S, Kwok C, Waller PA, Stevanovic M, Weissenbach J, Mansour S, Young ID, Goodfellow PN et al.: Campomelic dysplasia and autosomal sex reversal caused by mutations in an SRY-related gene. Nature t 994, 372:525-530. In this innovative paper, the authors describe the cloning of a transtocation chromosome breakpoint from a sex-reversed patient with campomelic dysplasia, resulting in the recognition of SOX9, a SRY-related gene, as the cause of this condition.
56. •e
ThomasJT, Lin K, Nandedkar M, Camargo M, Cervenka J, Luyten FP: A human chondrodysplasia due to a mutation in a TGF-13 superfamily member. Nat Genet 1996, 12:315-317. The authors describe a mutation in CDMP-1, a cartilage derived morphogenetic protein closely related to the subfamily of bone morphogenetic proteins, in a family with the recessive acromesomelic chondrodysplasia, Hunter-Thompson type. 5Z
Nicholls AC, McCarron S, Narcisi P, Pope FM: Molecular abnormalities of type V collagen in Ehlers-Danlos syndrome. Am J Hum Genet 1994, 55:A233.