Wilkin D J, Bogaert R, Lachman R S, Rimoin D L, Eyre D R, Cohn D H
Ahmanson Pediatric Center, Steven Spielberg Pediatric Research Center, Cedars-Sinai Medical Center, Los Angeles, CA 90048.
Hum Mol Genet. 1994 Nov;3(11):1999-2003. doi: 10.1093/hmg/3.11.1999.
Kniest dysplasia is a moderately severe chondrodysplasia phenotype that results from mutations in the gene for type II collagen, COL2A1. Characteristics of the disorder include a short trunk and extremities, mid-face hypoplasia, cleft palate, myopia, retinal detachment, and hearing loss. Recently, deletions of all or part of exon 12 have been identified in individuals with Kniest dysplasia, suggesting that mutations within this region of the protein may primarily result in the Kniest dysplasia phenotype. We used SSCP to analyze an amplified genomic DNA fragment containing exon 12 from seven individuals with Kniest dysplasia. An abnormality was identified in one patient. DNA sequence analysis demonstrated that the patient was heterozygous for a G to A transition that implied substitution of glycine103 of the triple helical domain by aspartate. The mutation was not observed in DNA from either of the clinically unaffected parents of the proband. Protein microsequencing demonstrated expression of the abnormal allele in cartilage. These data demonstrate that point mutations which result in single amino acid substitutions can produce Kniest dysplasia and further support the hypothesis that alteration of a domain, which includes the region encoded by exon 12, in the type II collagen protein leads to this disorder.
克尼斯发育不全是一种中度严重的软骨发育异常表型，由II型胶原蛋白基因COL2A1的突变引起。该疾病的特征包括躯干和四肢短小、面中部发育不全、腭裂、近视、视网膜脱离和听力丧失。最近，在克尼斯发育不全患者中发现了外显子12全部或部分缺失，这表明该蛋白这一区域内的突变可能是导致克尼斯发育不全表型的主要原因。我们使用单链构象多态性分析（SSCP）来分析来自7名克尼斯发育不全患者的包含外显子12的扩增基因组DNA片段。在一名患者中发现了异常。DNA序列分析表明，该患者为G到A转换的杂合子，这意味着三螺旋结构域的甘氨酸103被天冬氨酸取代。在先证者临床未受影响的父母的DNA中均未观察到该突变。蛋白质微测序表明异常等位基因在软骨中表达。这些数据表明，导致单个氨基酸替代的点突变可产生克尼斯发育不全，并进一步支持以下假设：II型胶原蛋白中包括外显子12编码区域的一个结构域的改变会导致这种疾病。
