Elliott A M, Bocangel P, Reed M H, Greenberg C R
WRHA Program of Genetics and Metabolism, University of Manitoba, Winnipeg, Manitoba, Canada.
Genet Mol Res. 2010 Sep 8;9(3):1785-90. doi: 10.4238/vol9-3gmr897.
Pseudoachondroplasia (PSACH) is an autosomal dominant skeletal dysplasia, generally identified clinically at two years of age due to decreased linear growth and a waddling gait. Radiographic features include small and irregular epiphyses, with metaphyseal changes of the long bones and characteristic vertebral changes. Mutations in the COMP gene cause PSACH and some cases of multiple epiphyseal dysplasia. Mutations generally cluster in the calmodulin-like repeat regions of the gene. Mutations in exon 13 (encoding the seventh calmodulin-like repeat) have been associated with severe short stature (-6 SD) in PSACH. We examined an Inuit boy with PSACH and severe short stature. Height essentially remained at -1 SD on the PSACH growth curve (-7.5 SD on a normal growth curve at 10.5 years). Analysis of COMP in our patient revealed a previously undescribed heterozygous A>T substitution in exon 8, at nucleotide 812. This change in the sequence resulted in replacement of a highly conserved and negatively charged aspartic acid with an uncharged, hydrophobic valine at amino acid position 271. Both unaffected parents were negative for this genetic change. This exon encodes the first calmodulin-like repeat, which has not been previously implicated in severe short stature. We propose that this novel missense substitution is responsible for the phenotype of this patient.
假性软骨发育不全（PSACH）是一种常染色体显性遗传性骨骼发育不良疾病，通常在患儿两岁时因线性生长减缓及蹒跚步态而在临床上得以确诊。X线特征包括骨骺小且不规则，长骨干骺端改变以及特征性的椎体改变。COMP基因突变会导致PSACH以及一些多发性骨骺发育不良病例。突变通常集中在该基因的钙调蛋白样重复区域。外显子13（编码第七个钙调蛋白样重复序列）中的突变与PSACH患者的严重身材矮小（-6标准差）有关。我们检查了一名患有PSACH和严重身材矮小的因纽特男孩。其身高在PSACH生长曲线上基本保持在-1标准差（10.5岁时在正常生长曲线上为-7.5标准差）。对我们这位患者的COMP分析显示，在外显子8的第812位核苷酸处存在一个此前未描述过的杂合A>T替换。该序列变化导致在氨基酸位置271处，一个高度保守且带负电荷的天冬氨酸被一个不带电荷的疏水性缬氨酸所取代。两位未受影响的父母均不存在这种基因变化。该外显子编码第一个钙调蛋白样重复序列，此前尚未发现其与严重身材矮小有关。我们认为这种新的错义替换是导致该患者表型的原因。
