ADAMTS10 mutations in autosomal recessive Weill-Marchesani syndrome
ADAMTS10 mutations in autosomal recessive Weill-Marchesani syndrome
复制标题
DOI：
10.1086/425231
复制
发表时间：
2004-11-01
影响因子：
9.8
通讯作者：
Cormier-Daire, V
中科院分区：
文献类型：
--
作者：
Dagoneau, N;Benoist-Lasselin, C;Cormier-Daire, V
Weill-Marchesani综合征(WMS)的特征是身材矮小、指短、关节僵硬、眼睛异常，包括微球晶状体和晶状体异位，偶尔还会有心脏缺陷。我们最近在染色体19p13.3-p13.2上定位了常染色体隐性遗传型WMS的一个基因，间隔为12.4 cM。在这里，我们报告了编码ADAMTS10的细胞外基质蛋白家族的一个成员的零突变，ADAMTS10是一种带有凝血酶反应蛋白基序的去整合素和金属蛋白酶。在2个有血缘关系的家系和1例散发性WMS患者中，共发现3个不同的突变，包括1个无义突变(R237X)和2个剪接突变(1190+1G-->；A和810+1G-->；A)。逆转录聚合酶链式反应、Northern印迹和斑点印迹分析表明，ADAMTS10在皮肤、胎儿软骨细胞、胎儿和成人心脏中均有表达。此外，对患者皮肤成纤维细胞的电子显微镜和免疫学研究证实，细胞外基质受损。因此，我们得出结论，ADAMTS10在人类的生长发育以及皮肤、晶状体和心脏的发育中发挥着重要作用。
Weill-Marchesani syndrome (WMS) is characterized by the association of short stature; brachydactyly; joint stiffness; eye anomalies, including microspherophakia and ectopia of the lenses; and, occasionally, heart defects. We have recently mapped a gene for the autosomal recessive form of WMS to chromosome 19p13.3-p13.2, in a 12.4-cM interval. Here, we report null mutations in a member of the extracellular matrix protease family, the gene encoding ADAMTS10, a disintegrin and metalloprotease with thrombospondin motifs. A total of three distinct mutations were identified in two consanguineous families and in one sporadic WMS case, including one nonsense mutation (R237X) and two splice mutations (1190+1G-->A and 810+1G-->A). ADAMTS10 expression studies using reverse-transcriptase polymerase chain reaction, northern blot, and dot-blot analyses showed that ADAMTS10 is expressed in skin, fetal chondrocytes, and fetal and adult heart. Moreover, electron microscopy and immunological studies of the skin fibroblasts from the patients confirmed impairment of the extracellular matrix. We conclude, therefore, that ADAMTS10 plays a major role in growth and in skin, lens, and heart development in humans.