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A G560S mutation in α1 (I) collagen causes familial osteogenesis imperfecta type IV
Clinica Chimica Acta 409 (2009) 145–146
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Clinica Chimica Acta j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / c l i n c h i m
Letter to the Editor A G560S mutation in α1 (I) collagen causes familial osteogenesis imperfecta type IV Dear Editor, Osteogenesis imperfecta (OI) is a heterogeneous group of inherited disorders characterized by a variable propensity for skeletal fractures following mild trauma. To date, 7 types of OI have been proposed based on clinical and histological findings, and these exhibit both autosomal dominant and recessive inheritance patterns. The dominant inherited forms that account for ~90% of OI patients result from heterozygous mutations in COL1A1 and COL1A2, genes on chromosome 17q21.3–17q22 and chromosome 7q22.1, respectively, encoding the proα1 (I) and proα2 (I) chains of type I collagen. Recessively inherited OI results, in many cases, from homozygous or compound heterozygous mutations in the CRTAP and LEPRE1 genes [1–3] that encode cartilage-associated protein, and leucine prolineenriched proteoglycan (leprecan and prolyl 3-hydroxylase 1), respectively. The traditional classification for OI was introduced by Sillence et al. [4], and distinguishes four main clinical phenotypes (OI I, OMIM #166200; OI II, OMIM #66210; OI III, OMIM #259420; OI IV, OMIM #166220). However, there is no clear correlation between the clinical phenotypes and the molecular mutations of type I collagen. We investigated 6 affected individuals over three generations in a Chinese family with an apparently autosomal dominant form of OI type IV (Fig. 1). All affected individuals in the family exhibited clinical features of OI, including a variable propensity for skeletal fractures and short stature as well as opalescent and translucent teeth, allowing a clinical diagnosis of OI type IV. Intriguingly, clinical variability was observed from affected individuals in the family. Three affected individuals, the grandmother (I-2), the mother (II-2) and the uncle (II-7) showed more severe phenotypes than the other cases. Two patients (II-2 and II-7) have difficulty walking and have been bedridden or wheelchair-bound for 6 and 2 years, respectively, because of bone pain and stiffness. The grandmother died in 2003 following a lengthy illness. The other 3 affected individuals (II-8, III-1 and III-2) are able to do housework and have a relatively normal quality of life. In addition, the mother (II-2) was diagnosed at 52 years as having mixed hearing loss, at 67 and 52 decibels in the right and left ears, by audiometric evaluation. The grandmother (I-2) also manifested bilateral progressive hearing loss after the fifth decade of her life. The affected members in the family who were younger than 50 years (II-7, II-8, III-1 and III-2) and all unaffected members including 2 individuals (II-3 and II-5) >50 years were without hearing loss. The detailed clinical data are summarized in Table 1. After approval by the Ethical Review Board of the Nanjing University Medical Center and informed consent, DNA from blood samples of all affected individuals and unaffected relatives of the family was extracted and amplified to detect microsatellite polymorphisms at loci D17S1299 and D7S1799 that are linked with the COL1A1 and COL1A2, respectively. Two-point LOD scores were calculated using the MLINK subprogram of the Linkage package (ver. 5.1). The results suggested that COL1A1 gene was a candidate gene (Zmax = 2.709, θ = 0.00, locus D17S1299) and 0009-8981/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.cca.2009.09.008
COL1A2 gene excluded (Zmax = −1.907, θ = 0.00, locus D7S1799). Subsequently, a heterozygous substitution of g.7601 G > A in exon 25 of COL1A1 was found by DNA sequencing in all affected individuals and was further confirmed by DHPLC analysis. The mutation resulted in a change from glycine to serine at amino acid residue 560 (p. G560S) in the α1 (I) chain. The heterozygous substitution was not observed in 11 unaffected individuals or 50 normal controls. All results indicated that G560S in the α1 (I) chain was the causative mutation for the familial OI. Hundreds of mutations in COL1A1 (OMIM #120150) and COL1A2 (OMIM #120160) have been detected in patients with OI (http://www. le.ac.uk/genetics/collagen). However, to our knowledge, the mutation reported here had been proposed only by Mackey et al. [5] who reported a sporadic case in a six-year-old child without detailed clinical description. The affected individuals in the family we reported have, in general, mild to moderate OI phenotypes. Intriguingly, they share the same mutation but show heterogeneous phenotypes. Three patients (I-2, II-2 and II-7) had more severe features than other cases (II-8, III-1, and III-2), including short stature, thoracolumbar scoliosis and osteoporosis. This phenotypic severity might be due to immobilization of these patients, resulting from severe chronic bone pain. Lying in bed for a long time may have further resulted in stiffness, short stature, muscular weakness and bone loss, which aggravated the thoracolumbar scoliosis, and increased fracture risk. Chronic bone pain seems to have been the main reason for the immobilization, so we advised the use of bisphosphonate. The clinical effect is still under observation. Progressive hearing loss is one of the principal symptoms of OI, and it typically begins in early adulthood [6]. In most cases, the onset of hearing impairment is noted in the second, third and fourth decades of life. At the age of 50 years, approximately 50% of OI patients have symptoms of hearing impairment [7,8], which proceeds from a conductive hearing loss to a mixed or sensorineural type [9–11]. The genetic basis of hearing loss in OI is complex, heterogeneous and multifactorial, and is still unknown because various types of hearing loss can be found in a single family [12]. In contrast, different mutation types found in different individuals result in overlapping hearing phenotypes [13]. Analysis has suggested no straightforward correlation between the mutated loci of COL1A1 and the types of hearing loss, the age of hearing loss onset, or the severity of hearing loss in patients with OI [13]. Therefore, it is suggested that alterations in any of several genetic or non-genetic factors may play an important role in modulating the hearing phenotype in OI patients. In the family described here, four patients (II-7, II-8, III-1 and III-2) had normal hearing. Apparently, the mutation is not sufficient to result in hearing impairment in younger patients in this family, but these affected individuals are at risk for delayed-onset hearing loss. Interpretation of the molecular data and detailed clinical features will be useful for clinical follow-up and genetic counseling.
Acknowledgements This work was supported by the Key Foundation of Jiangsu Science and Technology Bureau (BM2008151).
146
Letter to the Editor
Fig. 1. Family pedigree of osteogenesis imperfecta type IV. Black symbols indicate affected individuals and white ones indicate unaffected individuals. The arrow indicates the proband.
Table 1 Summary of the main features of the affected individuals in the family. Patient
Age (year)
Sex
Height (cm)
Hearing loss
No. of fracture
Bone pain/stiffness
Osteoporosis
Thoracolumbar scoliosis
I-2 II-2 II-7 II-8 III-1 III-2
72 58 40 38 38 34
F F M F M M
124 120 124 149 149 150
Present Present Absent Absent Absent Absent
2 3 8 1 1 1
Severe Severe Severe Mild Mild Mild
Severe Severe Severe Mild Mild Mild
Unknown Severe Severe Mild Mild Mild
References [1] Cabral WA, Chang W, Barnes AM, et al. Prolyl 3-hydroxylase 1 deficiency causes a recessive metabolic bone disorder resembling lethal/severe osteogenesis imperfecta. Nat Genet 2007;39:359–65. [2] Barnes AM, Chang W, Morello R, et al. Deficiency of cartilage-associated protein in recessive lethal osteogenesis imperfecta. N Engl J Med 2006;355:2757–64. [3] Morello R, Bertin TK, Chen Y, et al. CRTAP is required for prolyl 3-hydroxylation and mutations cause recessive osteogenesis imperfecta. Cell 2006;127:291–304. [4] Sillence DO, Senn A, Danks DM. Genetic heterogeneity in osteogenesis imperfecta. J Med Genet 1979;16:101–16. [5] Mackay K, Byers PH, Dalgleish R. An RT-PCR-SSCP screening strategy for detection of mutations in the gene encoding the alpha 1 chain of type I collagen: application to four patients with osteogenesis imperfecta. Hum Mol Genet 1993;2: 1155–60. [6] Imani P, Vijayasekaran S, Lannigan F. Is it necessary to screen for hearing loss in the paediatric population with osteogenesis imperfecta? Clin Otolaryngol Allied Sci 2003;28:199–202. [7] Kuurila K, Grénman R, Johansson R, Kaitila I. Hearing loss in children with osteogenesis imperfecta. Eur J Pediatr 2000;159:515–9. [8] Paterson CR, Monk EA, McAllion SJ. How common is hearing impairment in osteogenesis imperfecta? Laryngol Otol 2001;115:280–2. [9] Pedersen U. Hearing loss in patients with osteogenesis imperfecta. A clinical and audiological study of 201 patients. Scand Audiol 1984;13:67–74. [10] Garretsen AJ, Cremers CW, Huygén PL. Hearing loss (in nonoperated ears) in relation to age in osteogenesis imperfecta type I. Ann Otol Rhinol Laryngol 1997;106:575–82. [11] Kuurila K, Kaitila I, Johansson R, Grénman R. Hearing loss in Finnish adults with osteogenesis imperfecta: a nationwide survey. Ann Otol Rhinol Laryngol 2002;111:939–46. [12] Topolska MM. Hearing loss in osteogenesis imperfecta–casuistic demonstration. Otolaryngol Pol 2006;60:51–3.
[13] Hartikka H, Kuurila K, Körkkö J. Lack of correlation between the type of COL1A1 or COL1A2 mutation and hearing loss in osteogenesis imperfecta patients. Hum Mutat 2004;24:147–54.
Ying-Xia Cui1 Xin-Yi Xia1 Yi-Chao Shi Li Wei Quan Liang Bing Yao Yi-Feng Ge Yu-Feng Huang Xiao-Jun Li⁎ Institute of Laboratory Medicine, Jinling Hospital, Nanjing University School of Medicine, PR China ⁎Corresponding author. Institute of Laboratory Medicine, Jinling Hospital, Nanjing University School of Medicine, 305 East Zhongshan Road, Nanjing 210002, PR China. Tel.: +86 25 80863084; fax: +86 25 84803061. E-mail address: [email protected] (X.-J. Li). 1 The first two authors contributed equally to this work. 2 July 2009
Contents lists available at ScienceDirect
Clinica Chimica Acta j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / c l i n c h i m
Letter to the Editor A G560S mutation in α1 (I) collagen causes familial osteogenesis imperfecta type IV Dear Editor, Osteogenesis imperfecta (OI) is a heterogeneous group of inherited disorders characterized by a variable propensity for skeletal fractures following mild trauma. To date, 7 types of OI have been proposed based on clinical and histological findings, and these exhibit both autosomal dominant and recessive inheritance patterns. The dominant inherited forms that account for ~90% of OI patients result from heterozygous mutations in COL1A1 and COL1A2, genes on chromosome 17q21.3–17q22 and chromosome 7q22.1, respectively, encoding the proα1 (I) and proα2 (I) chains of type I collagen. Recessively inherited OI results, in many cases, from homozygous or compound heterozygous mutations in the CRTAP and LEPRE1 genes [1–3] that encode cartilage-associated protein, and leucine prolineenriched proteoglycan (leprecan and prolyl 3-hydroxylase 1), respectively. The traditional classification for OI was introduced by Sillence et al. [4], and distinguishes four main clinical phenotypes (OI I, OMIM #166200; OI II, OMIM #66210; OI III, OMIM #259420; OI IV, OMIM #166220). However, there is no clear correlation between the clinical phenotypes and the molecular mutations of type I collagen. We investigated 6 affected individuals over three generations in a Chinese family with an apparently autosomal dominant form of OI type IV (Fig. 1). All affected individuals in the family exhibited clinical features of OI, including a variable propensity for skeletal fractures and short stature as well as opalescent and translucent teeth, allowing a clinical diagnosis of OI type IV. Intriguingly, clinical variability was observed from affected individuals in the family. Three affected individuals, the grandmother (I-2), the mother (II-2) and the uncle (II-7) showed more severe phenotypes than the other cases. Two patients (II-2 and II-7) have difficulty walking and have been bedridden or wheelchair-bound for 6 and 2 years, respectively, because of bone pain and stiffness. The grandmother died in 2003 following a lengthy illness. The other 3 affected individuals (II-8, III-1 and III-2) are able to do housework and have a relatively normal quality of life. In addition, the mother (II-2) was diagnosed at 52 years as having mixed hearing loss, at 67 and 52 decibels in the right and left ears, by audiometric evaluation. The grandmother (I-2) also manifested bilateral progressive hearing loss after the fifth decade of her life. The affected members in the family who were younger than 50 years (II-7, II-8, III-1 and III-2) and all unaffected members including 2 individuals (II-3 and II-5) >50 years were without hearing loss. The detailed clinical data are summarized in Table 1. After approval by the Ethical Review Board of the Nanjing University Medical Center and informed consent, DNA from blood samples of all affected individuals and unaffected relatives of the family was extracted and amplified to detect microsatellite polymorphisms at loci D17S1299 and D7S1799 that are linked with the COL1A1 and COL1A2, respectively. Two-point LOD scores were calculated using the MLINK subprogram of the Linkage package (ver. 5.1). The results suggested that COL1A1 gene was a candidate gene (Zmax = 2.709, θ = 0.00, locus D17S1299) and 0009-8981/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.cca.2009.09.008
COL1A2 gene excluded (Zmax = −1.907, θ = 0.00, locus D7S1799). Subsequently, a heterozygous substitution of g.7601 G > A in exon 25 of COL1A1 was found by DNA sequencing in all affected individuals and was further confirmed by DHPLC analysis. The mutation resulted in a change from glycine to serine at amino acid residue 560 (p. G560S) in the α1 (I) chain. The heterozygous substitution was not observed in 11 unaffected individuals or 50 normal controls. All results indicated that G560S in the α1 (I) chain was the causative mutation for the familial OI. Hundreds of mutations in COL1A1 (OMIM #120150) and COL1A2 (OMIM #120160) have been detected in patients with OI (http://www. le.ac.uk/genetics/collagen). However, to our knowledge, the mutation reported here had been proposed only by Mackey et al. [5] who reported a sporadic case in a six-year-old child without detailed clinical description. The affected individuals in the family we reported have, in general, mild to moderate OI phenotypes. Intriguingly, they share the same mutation but show heterogeneous phenotypes. Three patients (I-2, II-2 and II-7) had more severe features than other cases (II-8, III-1, and III-2), including short stature, thoracolumbar scoliosis and osteoporosis. This phenotypic severity might be due to immobilization of these patients, resulting from severe chronic bone pain. Lying in bed for a long time may have further resulted in stiffness, short stature, muscular weakness and bone loss, which aggravated the thoracolumbar scoliosis, and increased fracture risk. Chronic bone pain seems to have been the main reason for the immobilization, so we advised the use of bisphosphonate. The clinical effect is still under observation. Progressive hearing loss is one of the principal symptoms of OI, and it typically begins in early adulthood [6]. In most cases, the onset of hearing impairment is noted in the second, third and fourth decades of life. At the age of 50 years, approximately 50% of OI patients have symptoms of hearing impairment [7,8], which proceeds from a conductive hearing loss to a mixed or sensorineural type [9–11]. The genetic basis of hearing loss in OI is complex, heterogeneous and multifactorial, and is still unknown because various types of hearing loss can be found in a single family [12]. In contrast, different mutation types found in different individuals result in overlapping hearing phenotypes [13]. Analysis has suggested no straightforward correlation between the mutated loci of COL1A1 and the types of hearing loss, the age of hearing loss onset, or the severity of hearing loss in patients with OI [13]. Therefore, it is suggested that alterations in any of several genetic or non-genetic factors may play an important role in modulating the hearing phenotype in OI patients. In the family described here, four patients (II-7, II-8, III-1 and III-2) had normal hearing. Apparently, the mutation is not sufficient to result in hearing impairment in younger patients in this family, but these affected individuals are at risk for delayed-onset hearing loss. Interpretation of the molecular data and detailed clinical features will be useful for clinical follow-up and genetic counseling.
Acknowledgements This work was supported by the Key Foundation of Jiangsu Science and Technology Bureau (BM2008151).
146
Letter to the Editor
Fig. 1. Family pedigree of osteogenesis imperfecta type IV. Black symbols indicate affected individuals and white ones indicate unaffected individuals. The arrow indicates the proband.
Table 1 Summary of the main features of the affected individuals in the family. Patient
Age (year)
Sex
Height (cm)
Hearing loss
No. of fracture
Bone pain/stiffness
Osteoporosis
Thoracolumbar scoliosis
I-2 II-2 II-7 II-8 III-1 III-2
72 58 40 38 38 34
F F M F M M
124 120 124 149 149 150
Present Present Absent Absent Absent Absent
2 3 8 1 1 1
Severe Severe Severe Mild Mild Mild
Severe Severe Severe Mild Mild Mild
Unknown Severe Severe Mild Mild Mild
References [1] Cabral WA, Chang W, Barnes AM, et al. Prolyl 3-hydroxylase 1 deficiency causes a recessive metabolic bone disorder resembling lethal/severe osteogenesis imperfecta. Nat Genet 2007;39:359–65. [2] Barnes AM, Chang W, Morello R, et al. Deficiency of cartilage-associated protein in recessive lethal osteogenesis imperfecta. N Engl J Med 2006;355:2757–64. [3] Morello R, Bertin TK, Chen Y, et al. CRTAP is required for prolyl 3-hydroxylation and mutations cause recessive osteogenesis imperfecta. Cell 2006;127:291–304. [4] Sillence DO, Senn A, Danks DM. Genetic heterogeneity in osteogenesis imperfecta. J Med Genet 1979;16:101–16. [5] Mackay K, Byers PH, Dalgleish R. An RT-PCR-SSCP screening strategy for detection of mutations in the gene encoding the alpha 1 chain of type I collagen: application to four patients with osteogenesis imperfecta. Hum Mol Genet 1993;2: 1155–60. [6] Imani P, Vijayasekaran S, Lannigan F. Is it necessary to screen for hearing loss in the paediatric population with osteogenesis imperfecta? Clin Otolaryngol Allied Sci 2003;28:199–202. [7] Kuurila K, Grénman R, Johansson R, Kaitila I. Hearing loss in children with osteogenesis imperfecta. Eur J Pediatr 2000;159:515–9. [8] Paterson CR, Monk EA, McAllion SJ. How common is hearing impairment in osteogenesis imperfecta? Laryngol Otol 2001;115:280–2. [9] Pedersen U. Hearing loss in patients with osteogenesis imperfecta. A clinical and audiological study of 201 patients. Scand Audiol 1984;13:67–74. [10] Garretsen AJ, Cremers CW, Huygén PL. Hearing loss (in nonoperated ears) in relation to age in osteogenesis imperfecta type I. Ann Otol Rhinol Laryngol 1997;106:575–82. [11] Kuurila K, Kaitila I, Johansson R, Grénman R. Hearing loss in Finnish adults with osteogenesis imperfecta: a nationwide survey. Ann Otol Rhinol Laryngol 2002;111:939–46. [12] Topolska MM. Hearing loss in osteogenesis imperfecta–casuistic demonstration. Otolaryngol Pol 2006;60:51–3.
[13] Hartikka H, Kuurila K, Körkkö J. Lack of correlation between the type of COL1A1 or COL1A2 mutation and hearing loss in osteogenesis imperfecta patients. Hum Mutat 2004;24:147–54.
Ying-Xia Cui1 Xin-Yi Xia1 Yi-Chao Shi Li Wei Quan Liang Bing Yao Yi-Feng Ge Yu-Feng Huang Xiao-Jun Li⁎ Institute of Laboratory Medicine, Jinling Hospital, Nanjing University School of Medicine, PR China ⁎Corresponding author. Institute of Laboratory Medicine, Jinling Hospital, Nanjing University School of Medicine, 305 East Zhongshan Road, Nanjing 210002, PR China. Tel.: +86 25 80863084; fax: +86 25 84803061. E-mail address: [email protected] (X.-J. Li). 1 The first two authors contributed equally to this work. 2 July 2009