An amino acid substitution (Gly853-->Glu) in the collagen alpha 1(II) chain produces hypochondrogenesis.
An amino acid substitution (Gly853-->Glu) in the collagen alpha 1(II) chain produces hypochondrogenesis.
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DOI：
10.1016/s0021-9258(18)41703-6
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发表时间：
1992-11
期刊：
影响因子：
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通讯作者：
R. Bogaert;G. Tiller;MaryAnn Weis;H. Gruber;D. L. Rimoin;Daniel H. Cohn;D. Eyre
中科院分区：
文献类型：
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作者：
R. Bogaert;G. Tiller;MaryAnn Weis;H. Gruber;D. L. Rimoin;Daniel H. Cohn;D. Eyre
骨发育不良的脊椎骨骺发育不良亚分类包括软骨发育不全、软骨发育不良和先天性脊椎骨骺发育不良。这些疾病的表型表达范围从轻度到围产期致死形式。我们报告的检测和部分特征的缺陷，在II型胶原蛋白在围产期致命形式的软骨发育不良。十二烷基硫酸钠-聚丙烯酰胺中的CB肽（其中CB代表溴化氰）从II型胶原蛋白的患病软骨的电泳显示肽α 1（II）CB 10和翻译后过度修饰的主要肽（CB 8，CB 10，和CB 11）的证据的双峰带被视为一个延迟的电泳迁移率。用内切蛋白酶Asp-N消化肽CB 10;在反相高压液相色谱上，注意到异常流动性的片段。独特的肽D12的序列分析揭示了在三螺旋结构域的位置853处的单个氨基酸取代（Gly->Glu）。扩增的COL 2A 1 cDNA的序列分析证实了这一点，其揭示了10个克隆中的5个中的单核苷酸取代（GGA->GAA）。病变软骨的电子显微镜照片显示稀疏的细胞外基质和含有扩张的粗面内质网的软骨细胞，这表明突变蛋白的组装和分泌受损。该病例进一步证明了软骨发育不良的脊椎骨骺发育不良谱的分子基础为COL 2A 1突变。
The spondyloepiphyseal dysplasia subclassification of bone dysplasias includes achondrogenesis, hypochondrogenesis, and spondyloepiphyseal dysplasia congenita. The phenotypic expression of these disorders ranges from mild to perinatal lethal forms. We report the detection and partial characterization of a defect in type II collagen in a perinatal lethal form of hypochondrogenesis. Electrophoresis in sodium dodecyl sulfate-polyacrylamide of CB peptides (where CB represents cyanogen bromide) from type II collagen of the diseased cartilage showed a doublet band for peptide alpha 1(II)CB10 and evidence for post-translational overmodification of the major peptides (CB8, CB10, and CB11) seen as a retarded electrophoretic mobility. Peptide CB10 was digested by endoproteinase Asp-N; and on reverse-phase high pressure liquid chromatography, fragments of abnormal mobility were noted. Sequence analysis of a unique peptide D12 revealed a single amino acid substitution (Gly–>Glu) at position 853 of the triple helical domain. This was confirmed by sequence analysis of amplified COL2A1 cDNA, which revealed a single nucleotide substitution (GGA–>GAA) in 5 of 10 clones. Electron micrographs of the diseased cartilage showed a sparse extracellular matrix and chondrocytes containing dilated rough endoplasmic reticulum, which suggested impaired assembly and secretion of the mutant protein. This case further documents the molecular basis of the spondyloepiphyseal dysplasia spectrum of chondrodysplasias as mutations in COL2A1.