Novel types of COMP mutations and genotype-phenotype association in pseudoachondroplasia and multiple epiphyseal dysplasia

被引:49
作者
Mabuchi, A
Manabe, N
Haga, N
Kitoh, H
Ikeda, T
Kawaji, H
Tamai, K
Hamada, J
Nakamura, S
Brunetti-Pierri, N
Kimizuka, M
Takatori, Y
Nakamura, K
Nishimura, G
Ohashi, H
Ikegawa, S
机构
[1] Univ Tokyo, Inst Med Sci, RIKEN, Lab Bone & Joint Dis,SNP Res Ctr,Minato Ku, Tokyo 1088639, Japan
[2] Univ Tokyo, Dept Orthopaed Surg, Tokyo, Japan
[3] Nagoya Univ, Sch Med, Dept Orthopaed Surg, Nagoya, Aichi 466, Japan
[4] Sanyudo Hosp, Dept Orthopaed Surg, Yonezawa, Yamagata, Japan
[5] Teikyo Univ, Sch Med, Dept Orthopaed Surg, Tokyo 173, Japan
[6] Univ Naples Federico II, Dept Pediat, Naples, Italy
[7] Natl Rehabil Ctr Disabled Children, Dept Orthoped, Tokyo, Japan
[8] Saitama Childrens Med Ctr, Div Med Genet, Iwatsuki, Saitama, Japan
关键词
D O I
10.1007/s00439-002-0845-9
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
Mutations in the gene encoding cartilage oligomeric matrix protein (COMP) cause two skeletal dysplasias, pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (MED). More than 40 mutations have been identified; however, genotype-phenotype relationships are not well delineated. Further, mutations other than in-frame insertion/deletions and substitutions have not been found, and currently known mutations are clustered within relatively small regions. Here we report the identification of nine novel and three recurrent COMP mutations in PSACH and MED patients. These include two novel types of mutations; the first, a gross deletion spanning an exon-intron junction, causes an exon deletion. The second, a frameshift mutation that results in a truncation of the C-terminal domain, is the first known truncating mutation in the COMP gene. The remaining mutations, other than a novel exon 18 mutation, affected highly conserved aspartate or cysteine residues in the calmodulin-like repeat (CLR) region. Genotype-phenotype analysis revealed a correlation between the position and type of mutations and the severity of short stature. Mutations in the seventh CLR produced more severe short stature compared with mutations elsewhere in the CLRs (P = 0.0003) and elsewhere in the COMP gene (P = 0.0007). Patients carrying mutations within the five-aspartates repeat (aa 469-473) in the seventh CLR were extremely short (below -6 SD). Patients with deletion mutations were significantly shorter than those with substitution mutations (P = 0.0024). These findings expand the mutation spectrum of the COMP gene and highlight genotype-phenotype relationships, facilitating improved genetic diagnosis and analysis of COMP function in humans.
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页码:84 / 90
页数:7
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