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Jansen's metaphyseal chondrodysplasia
ELSEVIER
BRIEF REVIEWS Jansen’s Metaphyseal Chondrodysplasia
Gram et al. 1959, Jansen 1934, Kessel et al. 1992, Kruse and Schutz 1993, Rao et al. 1979, Silver-thorn et al. 1983). The description of affected mothers and daughters in two different families sug-
A Disorder Due to a PTH/PT.HrP Receptor Gene Mutation
gested, however, an autosomal dominant mode of inheritance (Chat-row and Poznanski 1984, Holthusen et al. 1975, Lenz 1969).
Harald Jiippner
Jansen’s metaphyseal chondrodysplasia (JMC) is a rare genetic disorder that is characterized by short-limbed dwarfism and severe, agonistindependent hypercalcemia. An activating PTH/PTHrP receptor mutation that results in constitutive CAMP accumulation was recently identified in the genomic DNA of a patient with this disorder. These findings provide a plausible explanation for the abnormal regulation of growth-plate chondrocytes and mineral ion homeostasis in JMC, and may have significant implications for understanding the broader bio(Trends Endocrinol Metab 1996; logical role of PTHrP and its receptor. 7:157-162).
Jansen’s metaphyseal chondrodysplasia (JMC), a rare form of short-limbed dwarfism secondary to severe growthplate abnormalities, was first described in 1934 (Jansen 1934). Asymptomatic hypercalcemia and hypophosphatemia had already been noted in Jansen’s first patient (De Haas et al. 1969), and in a subsequently described child with the same disorder (Cameron et al. 1954). It was not until the description of another patient in 1959 (Figure l), however, that an association between the abnormalities in endochondral bone formation and in mineral ion homeostasis was formally considered (Gram et al. 1959). At the time, the biochemical abnormalities could not readily be distinguished
from
those observed in primary thyroidism. An exploration tient’s neck, however, ous
abnormalities
TEM Vol. 7, No. 5, 1996
in calcium
were either “secondary
parathyroid
concluded
that
and phosphorus to the underlying
bone defect,” or related to “an undefined metabolic
disorder that gave rise to both
metaphyseal
and biochemical
changes”
(Gram et al. 1959). Subsequent studies in this and other patients showed that the concentrations are either
of circulating
low or undetectable
and Poznanski
PTH (Frame
1980, Holt 1969, Kessel
et al. 1992, Kruse and Schutz
1993, Rao
et al. 1979, Silver-thorn et al. 1983) and that the levels of PTH-related peptide (PTHrP)
Harald Jiippner is at the Endocrine Unit, Department of Medicine and Children’s Service, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
revealed no obvi-
of the
glands. It was therefore the changes
hyperparaof the pa-
had not abnormally
(Kruse and Schutz Most reported
increased
1993).
cases of JMC are spo-
radic (Cameron et al. 1954, De Haas et al. 1969, Frame and Poznanski 1980,
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On physical examination at birth, some patients appear to be normal (Gram et al. 1959, Silverthorn et al. 1983), whereas others show dysmorphic which can include microfeatures, gnathia, prominent eyes, high skull vault, hypertelorism, prominent cheeks, wide cranial sutures, and a high-arched palate (Charrow and Poznanski 1984, De Haas et al. 1969, Frame and Poznanski 1980, Kessel et al. 1992, Kruse and Schutz 1993). Owing to choanal atresia and/or rib fractures, patients often develop postpartum respiratory distress and require intubation. Radiological studies usually show marked rachitiform metaphyseal changes of the long bones, that is, widening, fraying, and cupping, which are best seen in the knee joints, and also show pathological fractures. However, distinct from the findings in rickets, metacarpals and metatarsals are also involved, and the base of the skull and the calvaria are sclerotic. Loss of the normal cortical outline, subperiosteal bone resorption, and generalized are reminiscent of the osteopenia changes seen in hyperparathyroidism. In the newborn period, blood calcium and phosphorus concentrations are typically in the upper normal range, while alkaline phosphatase activity, a marker of bone turnover, can already be elevated (Char-row and Poznanski 1984, Frame and Poznanski 1980, Kessel et al. 1992, Kruse and Schutz 1993, Rao et al. 1979, Silverthom et al. 1983). During the first years of life, patients decline progressively from their normal growth curves, and present with short stature and other findings, which may
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Figure 1. Patient with Jansen’s metaphyseal chondrodysplasia at age 5 (left) and 22 (right). From Frame and Poznanski (1980), with permission. include waddling gait, enlarged joints, prominent supraorbital ridges, frontonasal hyperplasia, and a bell-shaped thor-ax with widened costochondral junctions. The legs, in particular the tibiae, are typically bowed, and are short in comparison to the relatively long arms. Tooth development and enamel formation appear to be normal. Radiological studies during childhood show, in al-
most all tubular bones, irregular patches of partially calcified cartilage that protrude into the diaphyses. The changes at this stage of development are no longer reminiscent of rickets, and appear to persist until the onset of puberty. The spine and the vertebral bodies show no obvious abnormalities (Cameron et al. 1954, Charrow and Poznanski 1984, De Haas et al. 1969, Frame and Poznanski
Figure 2. Hand radiographs of the patient first described by Jansen; at age 10 (left) and 44
(right). From De Haas et al. (1969), with permission.
158
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ElsevierScience
1980, Kessel et al. 1992, Kruse and’ Schutz 1993, Rao et al. 1979, Silver-thorn et al. 1983). After adolescence, the irregular masses of cartilaginous tissue in the metaphyses gradually disappear (Figure 2). The ends of most tubular bones, however, remain expanded, deformed, and radiolucent, but a more normal trabecular pattern gradually emerges. The large calcified masses in the metaphyses turn into bone and result in the bulbous deformities. The base of the skull remains hyperostotic, and a partial hearing loss, noted in the follow-up report of Jansen’s original patient, was thought to be secondary to narrow internal auditory meatuses. Intelligence appears to be normal in all reported cases (Cameron et al. 1954, Charrow and Poznanski 1984, De Haas et al. 1969, Frame and Poznanski 1980, Kessel et al. 1992, Kruse and Schutz 1993, Rao et al. 1979, Silverthorn et al. 1983). The few available histological data of biopsy material from bones and/or growth plates show wide, irregular masses of abnormal, protruding cartilage, a lack of the regular columnar arrangement of the maturing cartilage cells, and a severe delay in endochondral ossification of the metaphyses. There is no excess osteoid, usually indicative of active rickets or osteomalacia, little or no vascularization of cartilage, and no evidence for osteitis fibrosa (Cameron et al. 1954). In contrast, bone specimens of adult JMC patients showed significant fibrosis, and extensive osteoblastic and osteoclastic activity throughout the cortex and the trabeculae. Furthermore, the bone trabeculae are usually thin with large areas of subtrabecular erosions and a marked overall increase in boneremodeling activity (Gram et al. 1959, Jaffe 1972). Severe but asymptomatic hypercalcemia-next to metaphyseal changes, the most prominent feature of JMCusually develops during the first months after birth and persists throughout life, being most pronounced during infancy and childhood. Frame and Poznanski (1980) postulated, in fact, that the diagnosis of JMC is in doubt if hypercalcemia is not present. Owing to the lack of severe mineral ion abnormalities and atypical radiological findings, the diagnosis of JMC was therefore challenged in some patients (Arroyo-Scotoliff 1973, Charrow and Poznanski 1984, Kikuchi
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et al. 1976). Total centrations
serum
can range
dL, and are thought
from
calcium
con-
11 to 17 mg/
to be caused
by
increased osteoclast activity. Consistent with this assessment, urinary hydroxyproline excretion is markedly elevated. As a result of increased bone turnover, serum alkaline phosphatase activity and osteocalcin concentrations are elevated, and as the result of decreased tubular reabsorption, serum phosphate concentrations are decreased. Taken together, most laboratory findings in JMC are reminiscent of those in primary hyperparathyroidism or in the syndrome of malignancy-associated humoral hypercalcemia. Distinctly different from both these conditions, however, circulating concentrations of PTH and PTHrP are normal or undetectable, despite elevated urinary excretion of CAMP (De Haas et al. 1969, Frame and Poznanski 1980, Kessel et al. 1992, &use and Schtitz 1993, Rao et al. 1979, Silverthom et al. 1983). PTH is the major endocrine regulator of calcium homeostasis in mammals (Kronenberg et al. 1993). The biological role of PTHrP, first discovered as the major cause of the humoral hypercalcemia of malignancy, is still poorly defined. However, ablation of both PTHrP gene alleles in mice resulted in perinatal death and abnormal endochondml bone formation, and thus provided further compelling evidence for the peptide’s biological importance (Karaplis et al. 1994). PTH and PTHrP activate with similar efficacy the common PTH/PTHrP receptor, which belongs to a novel family of G protein-coupled receptors and signals through at least two second-messenger systems, adenylate cyclase and phospholipase C (Jtippner 1994). The mRNA encoding this receptor is found in a large variety of fetal and adult tissues. Receptor expression appears to be most abundant, however, in three major organs, that is, kidney, bone, and the metaphyseal growth plate (Lee et al. 1994 and 199.5, Tian et al. 1993, Urena et al. 1993). While PTH/PTHrP receptors on osteoblasts and renal epithelial cells mediate the endocrine actions of PTH and thus are involved in the control of mineral ion homeostasis, growth-plate chondrocytes are thought to mediate the paracrine/autocrine functions of PTHrP, which appear to be essential for normal endochondral bone formation (Amizuka
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intracellular
205
AVLILAYFRR AILIIGYFRR
LHCTRPJ’Y’IHM HLFLSFMLRA LHCTRPJYIHM HLFVSFMLRA
166
SMGIFLFFKN
LSCQRVTLHK
160 146 143
ALSILCSFRR AIAILVALRR AMAILSLFRK GSIIICLFRK
LHCTRNYIHM LHCPRNYIHT LHCTRNYIHM LHCTRNYIHL
152 160 162 170
ALLILSLFRR ALVILLGLRK ASAILVSFRH AMVILCRFRK
137 104
AFVLFLRLRS AVFVFLYFKD
162
161
VSIFVKDAVL TSIFVKDRW
PTH/PTHrP
NMFLTYILNS
IIIJIHLVEV
Calcitonin
HLFVSFILRA QLFATFILKA HLFMSFILRA NLFLSFMLRA
LSNFIKDAVL SAVFLKDAAV TAVFIKDMAL ISVLVKDSVL
LHCTRNYIHM LHCTRNYIHG LHCTRNYIHL LHCTRNFIHM
NLFTSFMLRA NLFASFVLKA NLFASFILRA NLFVSFMLRA
GAILTRDQLL GSVLVIDWLL LSVFIKDAAL ISVFIKDWIL
GIP Glucagon GLPl PACAP
IRCLRNIIHW LRCLRNTIHT
NLISAFILRN NLMSTYILSA
ATWFV.VQ.L CSW1LNLV.L
CRF DH
PTH2
Secretin GHRH VIP1
VIP2
Figure 3. Schematic representation of the human PTH/PTHrP receptor and aligned partial amino-acid sequences of the members of this family of G protein-coupled receptors (Jiippner 1994, Usdin et al. 1995); the location of the H223R missense mutation that leads to constitutive receptor activation is indicated. DH, diuretic hormone).
et al. 1994, Broadus and Stewart 1994, Karaplis et al. 1994). Owing to the prominent expression of the PTH/PTHrP receptor in these three cell types, we considered the possibility that the changes in calcium/phosphorus homeostasis and the metaphyseal growth plates, typically observed in JMC, are caused by constitutively active PTH/PTHrP receptors. To search for the activating PTH/ PTHrP receptor mutations, genomic DNA of a patient with JMC (Kruse and Schutz 1993) was screened by temperature-gradient gel electrophoresis and/or direct nucleotide sequence analysis as described previously (Schipani et al. 1995b). A single heterozygous nucleotide change, adenine (A) to guanine (G), was identified in exon M2 of the PTH/PTHrP receptor gene, which changes a histidine at position 223 to arginine (Figure 3) (Schipani et al. 1995a). This histidine is located at the junction between the first intracellular loop and the second membrane-spanning helix, and is strictly conserved in all members of this receptor family (Juppner 1994), which suggested that this amino acid residue serves an important functional role. The identified A to G transition introduces a novel SphI re-
Elsevier Science Inc., 1043-2760/96/$15.00
striction site; Southern blot analysis of SphI-digested genomic DNA was therefore used to confirm the presence of the mutation in the patient and to exclude it in both healthy parents (Schipani et al. 1995a). The histidine to arginine mutation of the patient thus appears to represent a new germline mutation or a somatic mutation that occurred early in development. To test the functional consequences of this missense mutation in vitro, the corresponding nucleotide change was introduced by oligonucleotide-directed sitespecific mutagenesis into the cDNA encoding the wild-type human PTH/PTHrP receptor (Schipani et al. 1993). COS-7 cells transiently expressing the mutant receptor showed constitutive, ligand-independent CAMP accumulation that was approximately 5 times higher than the basal activity observed with the wildtype PTH/PTHrP receptor (Figure 4). When challenged with increasing concentrations of either PTH or PTHrP, CAMP accumulation increased only about twofold in COS-7 cells expressing the mutant receptor, whereas cells expressing the wild-type receptor showed an about 20-fold increase in CAMP accumulation. Basal inositol phosphate ac-
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1.59
biological role(s) that are mediated by the PTH/PTHrP receptor (Figure 5). As
outlinedhere,PTHlPTHrP receptorsare
-12 -11 -10
-9
-8
-7
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ligand [M] Figure 4. Insert: basal, agonist-independent CAMP accumulation by COS-7 cells transiently expressing the wild-type (solid bar) and the mutant PTH/PTHrP receptor (stippled bar); PTH(solid symbol) and PTHP-stimulated (open symboZ.s) accumulation of intracellular CAMP by cells expressing wild-type (squares) and mutant PlWPTHrP receptors (circles). Note that basal
CAMPaccumulation is approximately fivefold higher for cells expressing the mutant receptor than for cells expressing the wild-type PTH/PTHrP receptor. From Schipani et al. (1995a). with permission. cumulation was indistinguishable for cells expressing the wild-type and the mutant PTH/PTHrP receptor. Despite sufficient receptor expression on the cell surface, however, the latter cells failed, to increase inositol phosphate accumulation when challenged with PTH or PTHrP (Schipani et al. 1995a). Activating receptor mutations, that are similar to the one identified in the PTH/PTHrP receptor, were recently implicated in several other human diseases. For example, mutations in rhodopsin cause either rare forms of retinitis pigmentosa (Robinson et al. 1992) or congenital stationary blindness (Dryja et al. 1993). Thyroid adenomas (Parma et al. 1993) or nonautoimmune hyperthyroidism (Duprez et al. 1994, Kopp et al. 1995, Paschke et al. 1994, Tonacchera et al. 1996) can be caused by activating mutations in the TSH receptor. In the LH receptor, activating mutations cause gonadotropin-independent male precocious puberty (Kraaij et al. 1995, Latronico et al. 1995, Shenker et al. 1993), and mutations in the calciumsensing receptor cause a familial form of
160
01996,
hypoparathyroidism (Pollak et al. 1994). The constitutive active PTH/PTHrP receptor identified in a JMC patient thus extends the list of activating mutations to yet another family of G-protein coupled receptors. The molecular definition of JMC provides new insights for understanding the
abundantly expressed in bone and kidney. It is, therefore, very likely thatindependent of the circulating PTH concentrations-expression of the mutant, constitutively active PTH/PTHrP receptor causes the severe abnormalities in mineral ion homeostasis that are typically observed in patients with JMC (Charrow and Poznanski 1984, Frame and Poznanski 1980, Kessel et al. 1992, Kruse and Schutz 1993, Rae et al. 1979, Silver-thorn et al. 1983). Furthermore, the expression of constitutively active PTH/PTHrP receptors in metaphyseal chondrocytes (Lee et al. 1995) could also explain the growth-plate abnormalities (Figure 5). It has long been known that PTH affects chondrocyte maturation and activity (Lebovitz and Eisenbarth 1975, Smith et al. 1976). Recent studies have confirmed these earlier findings and showed that this ligand stimulates the proliferation of fetal growth-plate chondrocytes (Koike et al. 1990) sup presses their differentiation into hypertrophic cells, and stimulates the accumulation of cartilage-specific proteoglycans, which are thought to inhibit mineralization (Iwamoto et al. 1994, Takano et al. 1985). Furthermore, recent in vitro studies have shown that cell matrix production and terminal differentiation into hypertrophic chondrocytes is inhibited by CAMP analogues (Jikko et al. 1996). Although most earlier studies with cultured chondrocytes investigated the effect of PTH, it now appears more likely that
Figure 5. Biological role of the PTH/PTHrP receptor in the regulation of calcium ion homeo-
stasis and growth-plate chondrocytes; location of the activating missense mutation in a patient with Jansen’s metaphyserd chondrodysplasia is indicated by a white circle.
Pr--l I
Ca++
Cartilage other tissues ?
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PTHrP, locally produced by perichondml cells (Lee et al. 1995), is the natural ligand for the common
PTH/PTHrP
receptor, at
least in the growth plate. Consistent with such a prominent role of PTHrP in chondrocyte maturation,
mice in which either
the PTHrP gene or the PTH/PTHrP recep tor gene were ablated, show severe abnormalities of growth-plate development and premature mineralization (Kamplis et al. 1994, Lanske et al. 1994). Furthermore,
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Tonacchera M, van Sande J, Cetani F, et al.: 1996. Functional characteristics of three new germhne mutations of the thyrotropin receptor gene causing autosomal dominant toxic thyroid hyperplasia. J Clin Endocrinol Metab 81:547-554.
drodysplasia of Jansen (MCD): an enigma. In Norman AW, Schaefer K, von Herrath D, et al., eds. Vitamin D, Basic Research and Its Clinical Application. Berlin, Walter de Gruyter, pp 1173-l 176.
Schipani E, Weinstein LS, Bergwitz C, et al.: 1995b. Pseudohypoparathyroidism type Ib is not caused by mutations in the coding exons of the human parathyroid hormone (PTH)/ PTH-related peptide receptor gene. J CIin Endocrinol Metab 80:1611-1621. Shenker A, Laue L, Kosugi S, Merendino JJ Jr., Minegishi T, Cutler GB: 993. A constitutively activating mutation of the luteinizing hormone receptor in familial male precocious puberty. Nature 365:652454. Siiverthorn KG, Houston CS, Duncan BP1983. Murk Jansen’s metaphyseal chondrodysplasia with long-term followup. Pediatr Radio1 17:119-123. Smith DM, Roth LM, Johnston CC Jr: 1976. Hormonal responsiveness of adenylate cy&se activity in cartilage. Endocrinology 98: 242-246.
FOR COttEAGULS
Urena P, Kong XF, Abou-Samra AB, et al.: 1993. Parathyroid hormone (PTH)/PTH-related peptide (PTHrP) receptor mRNA are widely distributed in rat tissues. Endocrinology 133:617-623. Usdin TB, Gruber C, Bonner TI: 1995. Identification and functional expression of a receptor selectively recognizing parathyroid hormone, the PTH2 receptor. J Biol Chem 270: 15,455-15;458. Weir E, Philbrick W, Neff L, Amling M, Baron R, Broadus A: 1995. Targeted overexpression of parathyroid hormone-related peptide in chondrocytes causes skeletal dysplasia and delayed osteogenesis. J Bone Miner Res TEM lO(Supp1 l):S157.
AbRoAd
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BRIEF REVIEWS Jansen’s Metaphyseal Chondrodysplasia
Gram et al. 1959, Jansen 1934, Kessel et al. 1992, Kruse and Schutz 1993, Rao et al. 1979, Silver-thorn et al. 1983). The description of affected mothers and daughters in two different families sug-
A Disorder Due to a PTH/PT.HrP Receptor Gene Mutation
gested, however, an autosomal dominant mode of inheritance (Chat-row and Poznanski 1984, Holthusen et al. 1975, Lenz 1969).
Harald Jiippner
Jansen’s metaphyseal chondrodysplasia (JMC) is a rare genetic disorder that is characterized by short-limbed dwarfism and severe, agonistindependent hypercalcemia. An activating PTH/PTHrP receptor mutation that results in constitutive CAMP accumulation was recently identified in the genomic DNA of a patient with this disorder. These findings provide a plausible explanation for the abnormal regulation of growth-plate chondrocytes and mineral ion homeostasis in JMC, and may have significant implications for understanding the broader bio(Trends Endocrinol Metab 1996; logical role of PTHrP and its receptor. 7:157-162).
Jansen’s metaphyseal chondrodysplasia (JMC), a rare form of short-limbed dwarfism secondary to severe growthplate abnormalities, was first described in 1934 (Jansen 1934). Asymptomatic hypercalcemia and hypophosphatemia had already been noted in Jansen’s first patient (De Haas et al. 1969), and in a subsequently described child with the same disorder (Cameron et al. 1954). It was not until the description of another patient in 1959 (Figure l), however, that an association between the abnormalities in endochondral bone formation and in mineral ion homeostasis was formally considered (Gram et al. 1959). At the time, the biochemical abnormalities could not readily be distinguished
from
those observed in primary thyroidism. An exploration tient’s neck, however, ous
abnormalities
TEM Vol. 7, No. 5, 1996
in calcium
were either “secondary
parathyroid
concluded
that
and phosphorus to the underlying
bone defect,” or related to “an undefined metabolic
disorder that gave rise to both
metaphyseal
and biochemical
changes”
(Gram et al. 1959). Subsequent studies in this and other patients showed that the concentrations are either
of circulating
low or undetectable
and Poznanski
PTH (Frame
1980, Holt 1969, Kessel
et al. 1992, Kruse and Schutz
1993, Rao
et al. 1979, Silver-thorn et al. 1983) and that the levels of PTH-related peptide (PTHrP)
Harald Jiippner is at the Endocrine Unit, Department of Medicine and Children’s Service, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
revealed no obvi-
of the
glands. It was therefore the changes
hyperparaof the pa-
had not abnormally
(Kruse and Schutz Most reported
increased
1993).
cases of JMC are spo-
radic (Cameron et al. 1954, De Haas et al. 1969, Frame and Poznanski 1980,
01996, Ekevier Science Inc., 1043-2760/96/$15.00
On physical examination at birth, some patients appear to be normal (Gram et al. 1959, Silverthorn et al. 1983), whereas others show dysmorphic which can include microfeatures, gnathia, prominent eyes, high skull vault, hypertelorism, prominent cheeks, wide cranial sutures, and a high-arched palate (Charrow and Poznanski 1984, De Haas et al. 1969, Frame and Poznanski 1980, Kessel et al. 1992, Kruse and Schutz 1993). Owing to choanal atresia and/or rib fractures, patients often develop postpartum respiratory distress and require intubation. Radiological studies usually show marked rachitiform metaphyseal changes of the long bones, that is, widening, fraying, and cupping, which are best seen in the knee joints, and also show pathological fractures. However, distinct from the findings in rickets, metacarpals and metatarsals are also involved, and the base of the skull and the calvaria are sclerotic. Loss of the normal cortical outline, subperiosteal bone resorption, and generalized are reminiscent of the osteopenia changes seen in hyperparathyroidism. In the newborn period, blood calcium and phosphorus concentrations are typically in the upper normal range, while alkaline phosphatase activity, a marker of bone turnover, can already be elevated (Char-row and Poznanski 1984, Frame and Poznanski 1980, Kessel et al. 1992, Kruse and Schutz 1993, Rao et al. 1979, Silverthom et al. 1983). During the first years of life, patients decline progressively from their normal growth curves, and present with short stature and other findings, which may
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Figure 1. Patient with Jansen’s metaphyseal chondrodysplasia at age 5 (left) and 22 (right). From Frame and Poznanski (1980), with permission. include waddling gait, enlarged joints, prominent supraorbital ridges, frontonasal hyperplasia, and a bell-shaped thor-ax with widened costochondral junctions. The legs, in particular the tibiae, are typically bowed, and are short in comparison to the relatively long arms. Tooth development and enamel formation appear to be normal. Radiological studies during childhood show, in al-
most all tubular bones, irregular patches of partially calcified cartilage that protrude into the diaphyses. The changes at this stage of development are no longer reminiscent of rickets, and appear to persist until the onset of puberty. The spine and the vertebral bodies show no obvious abnormalities (Cameron et al. 1954, Charrow and Poznanski 1984, De Haas et al. 1969, Frame and Poznanski
Figure 2. Hand radiographs of the patient first described by Jansen; at age 10 (left) and 44
(right). From De Haas et al. (1969), with permission.
158
01996,
ElsevierScience
1980, Kessel et al. 1992, Kruse and’ Schutz 1993, Rao et al. 1979, Silver-thorn et al. 1983). After adolescence, the irregular masses of cartilaginous tissue in the metaphyses gradually disappear (Figure 2). The ends of most tubular bones, however, remain expanded, deformed, and radiolucent, but a more normal trabecular pattern gradually emerges. The large calcified masses in the metaphyses turn into bone and result in the bulbous deformities. The base of the skull remains hyperostotic, and a partial hearing loss, noted in the follow-up report of Jansen’s original patient, was thought to be secondary to narrow internal auditory meatuses. Intelligence appears to be normal in all reported cases (Cameron et al. 1954, Charrow and Poznanski 1984, De Haas et al. 1969, Frame and Poznanski 1980, Kessel et al. 1992, Kruse and Schutz 1993, Rao et al. 1979, Silverthorn et al. 1983). The few available histological data of biopsy material from bones and/or growth plates show wide, irregular masses of abnormal, protruding cartilage, a lack of the regular columnar arrangement of the maturing cartilage cells, and a severe delay in endochondral ossification of the metaphyses. There is no excess osteoid, usually indicative of active rickets or osteomalacia, little or no vascularization of cartilage, and no evidence for osteitis fibrosa (Cameron et al. 1954). In contrast, bone specimens of adult JMC patients showed significant fibrosis, and extensive osteoblastic and osteoclastic activity throughout the cortex and the trabeculae. Furthermore, the bone trabeculae are usually thin with large areas of subtrabecular erosions and a marked overall increase in boneremodeling activity (Gram et al. 1959, Jaffe 1972). Severe but asymptomatic hypercalcemia-next to metaphyseal changes, the most prominent feature of JMCusually develops during the first months after birth and persists throughout life, being most pronounced during infancy and childhood. Frame and Poznanski (1980) postulated, in fact, that the diagnosis of JMC is in doubt if hypercalcemia is not present. Owing to the lack of severe mineral ion abnormalities and atypical radiological findings, the diagnosis of JMC was therefore challenged in some patients (Arroyo-Scotoliff 1973, Charrow and Poznanski 1984, Kikuchi
Inc., 1043-2760/96/$15OilPII SlO43-2760(96)00063-X
TEA4 Vol. 7, No. 5, 1996
et al. 1976). Total centrations
serum
can range
dL, and are thought
from
calcium
con-
11 to 17 mg/
to be caused
by
increased osteoclast activity. Consistent with this assessment, urinary hydroxyproline excretion is markedly elevated. As a result of increased bone turnover, serum alkaline phosphatase activity and osteocalcin concentrations are elevated, and as the result of decreased tubular reabsorption, serum phosphate concentrations are decreased. Taken together, most laboratory findings in JMC are reminiscent of those in primary hyperparathyroidism or in the syndrome of malignancy-associated humoral hypercalcemia. Distinctly different from both these conditions, however, circulating concentrations of PTH and PTHrP are normal or undetectable, despite elevated urinary excretion of CAMP (De Haas et al. 1969, Frame and Poznanski 1980, Kessel et al. 1992, &use and Schtitz 1993, Rao et al. 1979, Silverthom et al. 1983). PTH is the major endocrine regulator of calcium homeostasis in mammals (Kronenberg et al. 1993). The biological role of PTHrP, first discovered as the major cause of the humoral hypercalcemia of malignancy, is still poorly defined. However, ablation of both PTHrP gene alleles in mice resulted in perinatal death and abnormal endochondml bone formation, and thus provided further compelling evidence for the peptide’s biological importance (Karaplis et al. 1994). PTH and PTHrP activate with similar efficacy the common PTH/PTHrP receptor, which belongs to a novel family of G protein-coupled receptors and signals through at least two second-messenger systems, adenylate cyclase and phospholipase C (Jtippner 1994). The mRNA encoding this receptor is found in a large variety of fetal and adult tissues. Receptor expression appears to be most abundant, however, in three major organs, that is, kidney, bone, and the metaphyseal growth plate (Lee et al. 1994 and 199.5, Tian et al. 1993, Urena et al. 1993). While PTH/PTHrP receptors on osteoblasts and renal epithelial cells mediate the endocrine actions of PTH and thus are involved in the control of mineral ion homeostasis, growth-plate chondrocytes are thought to mediate the paracrine/autocrine functions of PTHrP, which appear to be essential for normal endochondral bone formation (Amizuka
TEM Vol. 7, No. 5, 1996
01996,
intracellular
205
AVLILAYFRR AILIIGYFRR
LHCTRPJ’Y’IHM HLFLSFMLRA LHCTRPJYIHM HLFVSFMLRA
166
SMGIFLFFKN
LSCQRVTLHK
160 146 143
ALSILCSFRR AIAILVALRR AMAILSLFRK GSIIICLFRK
LHCTRNYIHM LHCPRNYIHT LHCTRNYIHM LHCTRNYIHL
152 160 162 170
ALLILSLFRR ALVILLGLRK ASAILVSFRH AMVILCRFRK
137 104
AFVLFLRLRS AVFVFLYFKD
162
161
VSIFVKDAVL TSIFVKDRW
PTH/PTHrP
NMFLTYILNS
IIIJIHLVEV
Calcitonin
HLFVSFILRA QLFATFILKA HLFMSFILRA NLFLSFMLRA
LSNFIKDAVL SAVFLKDAAV TAVFIKDMAL ISVLVKDSVL
LHCTRNYIHM LHCTRNYIHG LHCTRNYIHL LHCTRNFIHM
NLFTSFMLRA NLFASFVLKA NLFASFILRA NLFVSFMLRA
GAILTRDQLL GSVLVIDWLL LSVFIKDAAL ISVFIKDWIL
GIP Glucagon GLPl PACAP
IRCLRNIIHW LRCLRNTIHT
NLISAFILRN NLMSTYILSA
ATWFV.VQ.L CSW1LNLV.L
CRF DH
PTH2
Secretin GHRH VIP1
VIP2
Figure 3. Schematic representation of the human PTH/PTHrP receptor and aligned partial amino-acid sequences of the members of this family of G protein-coupled receptors (Jiippner 1994, Usdin et al. 1995); the location of the H223R missense mutation that leads to constitutive receptor activation is indicated. DH, diuretic hormone).
et al. 1994, Broadus and Stewart 1994, Karaplis et al. 1994). Owing to the prominent expression of the PTH/PTHrP receptor in these three cell types, we considered the possibility that the changes in calcium/phosphorus homeostasis and the metaphyseal growth plates, typically observed in JMC, are caused by constitutively active PTH/PTHrP receptors. To search for the activating PTH/ PTHrP receptor mutations, genomic DNA of a patient with JMC (Kruse and Schutz 1993) was screened by temperature-gradient gel electrophoresis and/or direct nucleotide sequence analysis as described previously (Schipani et al. 1995b). A single heterozygous nucleotide change, adenine (A) to guanine (G), was identified in exon M2 of the PTH/PTHrP receptor gene, which changes a histidine at position 223 to arginine (Figure 3) (Schipani et al. 1995a). This histidine is located at the junction between the first intracellular loop and the second membrane-spanning helix, and is strictly conserved in all members of this receptor family (Juppner 1994), which suggested that this amino acid residue serves an important functional role. The identified A to G transition introduces a novel SphI re-
Elsevier Science Inc., 1043-2760/96/$15.00
striction site; Southern blot analysis of SphI-digested genomic DNA was therefore used to confirm the presence of the mutation in the patient and to exclude it in both healthy parents (Schipani et al. 1995a). The histidine to arginine mutation of the patient thus appears to represent a new germline mutation or a somatic mutation that occurred early in development. To test the functional consequences of this missense mutation in vitro, the corresponding nucleotide change was introduced by oligonucleotide-directed sitespecific mutagenesis into the cDNA encoding the wild-type human PTH/PTHrP receptor (Schipani et al. 1993). COS-7 cells transiently expressing the mutant receptor showed constitutive, ligand-independent CAMP accumulation that was approximately 5 times higher than the basal activity observed with the wildtype PTH/PTHrP receptor (Figure 4). When challenged with increasing concentrations of either PTH or PTHrP, CAMP accumulation increased only about twofold in COS-7 cells expressing the mutant receptor, whereas cells expressing the wild-type receptor showed an about 20-fold increase in CAMP accumulation. Basal inositol phosphate ac-
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1.59
biological role(s) that are mediated by the PTH/PTHrP receptor (Figure 5). As
outlinedhere,PTHlPTHrP receptorsare
-12 -11 -10
-9
-8
-7
-6
ligand [M] Figure 4. Insert: basal, agonist-independent CAMP accumulation by COS-7 cells transiently expressing the wild-type (solid bar) and the mutant PTH/PTHrP receptor (stippled bar); PTH(solid symbol) and PTHP-stimulated (open symboZ.s) accumulation of intracellular CAMP by cells expressing wild-type (squares) and mutant PlWPTHrP receptors (circles). Note that basal
CAMPaccumulation is approximately fivefold higher for cells expressing the mutant receptor than for cells expressing the wild-type PTH/PTHrP receptor. From Schipani et al. (1995a). with permission. cumulation was indistinguishable for cells expressing the wild-type and the mutant PTH/PTHrP receptor. Despite sufficient receptor expression on the cell surface, however, the latter cells failed, to increase inositol phosphate accumulation when challenged with PTH or PTHrP (Schipani et al. 1995a). Activating receptor mutations, that are similar to the one identified in the PTH/PTHrP receptor, were recently implicated in several other human diseases. For example, mutations in rhodopsin cause either rare forms of retinitis pigmentosa (Robinson et al. 1992) or congenital stationary blindness (Dryja et al. 1993). Thyroid adenomas (Parma et al. 1993) or nonautoimmune hyperthyroidism (Duprez et al. 1994, Kopp et al. 1995, Paschke et al. 1994, Tonacchera et al. 1996) can be caused by activating mutations in the TSH receptor. In the LH receptor, activating mutations cause gonadotropin-independent male precocious puberty (Kraaij et al. 1995, Latronico et al. 1995, Shenker et al. 1993), and mutations in the calciumsensing receptor cause a familial form of
160
01996,
hypoparathyroidism (Pollak et al. 1994). The constitutive active PTH/PTHrP receptor identified in a JMC patient thus extends the list of activating mutations to yet another family of G-protein coupled receptors. The molecular definition of JMC provides new insights for understanding the
abundantly expressed in bone and kidney. It is, therefore, very likely thatindependent of the circulating PTH concentrations-expression of the mutant, constitutively active PTH/PTHrP receptor causes the severe abnormalities in mineral ion homeostasis that are typically observed in patients with JMC (Charrow and Poznanski 1984, Frame and Poznanski 1980, Kessel et al. 1992, Kruse and Schutz 1993, Rae et al. 1979, Silver-thorn et al. 1983). Furthermore, the expression of constitutively active PTH/PTHrP receptors in metaphyseal chondrocytes (Lee et al. 1995) could also explain the growth-plate abnormalities (Figure 5). It has long been known that PTH affects chondrocyte maturation and activity (Lebovitz and Eisenbarth 1975, Smith et al. 1976). Recent studies have confirmed these earlier findings and showed that this ligand stimulates the proliferation of fetal growth-plate chondrocytes (Koike et al. 1990) sup presses their differentiation into hypertrophic cells, and stimulates the accumulation of cartilage-specific proteoglycans, which are thought to inhibit mineralization (Iwamoto et al. 1994, Takano et al. 1985). Furthermore, recent in vitro studies have shown that cell matrix production and terminal differentiation into hypertrophic chondrocytes is inhibited by CAMP analogues (Jikko et al. 1996). Although most earlier studies with cultured chondrocytes investigated the effect of PTH, it now appears more likely that
Figure 5. Biological role of the PTH/PTHrP receptor in the regulation of calcium ion homeo-
stasis and growth-plate chondrocytes; location of the activating missense mutation in a patient with Jansen’s metaphyserd chondrodysplasia is indicated by a white circle.
Pr--l I
Ca++
Cartilage other tissues ?
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TEA4 Vol.7,No. 5,1996
PTHrP, locally produced by perichondml cells (Lee et al. 1995), is the natural ligand for the common
PTH/PTHrP
receptor, at
least in the growth plate. Consistent with such a prominent role of PTHrP in chondrocyte maturation,
mice in which either
the PTHrP gene or the PTH/PTHrP recep tor gene were ablated, show severe abnormalities of growth-plate development and premature mineralization (Kamplis et al. 1994, Lanske et al. 1994). Furthermore,
References Amizuka N, Warshawsky H, Henderson JE, Goltzman D, Karaplis AC: 1994. Parathyroid hormone-related peptidedepleted mice show abnormal epiphyseal cartilage development and altered endochonclrealbone formation. J Cell Biol 126:1611-1623. Arroyo-Scotoliff
I-k 1973. Metaphyseal
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