Dyssegmental dysplasia, Silverman-Handmaker type, is caused by functional null mutations of the perlecan gene
Dyssegmental dysplasia, Silverman-Handmaker type, is caused by functional null mutations of the perlecan gene
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DOI：
10.1038/86941
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发表时间：
2001-04-01
期刊：
影响因子：
30.8
通讯作者：
Yamada, Y
中科院分区：
文献类型：
--
作者：
Arikawa-Hirasawa, E;Wilcox, WR;Yamada, Y
串珠素是一种存在于所有基底膜和一些其他组织（如软骨）中的大硫酸乙酰肝素（HS）蛋白聚糖（1，2），并与细胞生长和分化有关（3-5）。缺乏串珠蛋白聚糖基因（6，7）（Hspg 2）的小鼠具有严重的软骨发育不良，伴有脊柱的节段性发育不良骨化，并且显示出与人类中称为节段性发育不良的Silverman-Handmaker型（DDSH; MIM 224410）的致死性常染色体隐性疾病相似的放射学、临床和软骨-骨形态学。我们在这里报道。在一对由近亲父母所生的患有DDSH的兄弟姐妹中，HSPG 2的外显子34中存在纯合的89-bp重复，并且在第三个无关患者中，在内含子52的5'供体位点和外显子73的中间存在杂合点突变，分别导致HSPG 2转录物的整个外显子52和73的跳跃。预计这些突变会引起移码，导致截短的蛋白质核心。这些患者的软骨基质用串珠素特异性抗体染色较差，但细胞内包涵体染色。在生物化学上，截短的串珠素不被患者成纤维细胞分泌，而是在细胞内降解成较小的片段。因此，DDSH是由HSPG 2的功能性无效突变引起的。我们的研究结果表明串珠素在软骨发育中的关键作用。
Perlecan is a large heparan sulfate (HS) proteoglycan present in all basement membranes and in some other tissues such as cartilage(1,2), and is implicated in cell growth and differentiation(3-5). Mice lacking the perlecan gene(6,7) (Hspg2) have a severe chondrodysplasia with dyssegmental ossification of the spine and show radiographic, clinical and chondro-osseous morphology similar to a lethal autosomal recessive disorder in humans termed dyssegmental dysplasia, Silverman-Handmaker type (DDSH; MIM 224410). Here we report. a homozygous, 89-bp duplication in exon 34 of HSPG2 in a pair of siblings with DDSH born to consanguineous parents, and heterozygous point mutations in the 5' donor site of intron 52 and in the middle of exon 73 in a third, unrelated patient, causing skipping of the entire exons 52 and 73 of the HSPG2 transcript, respectively. These mutations are predicted to cause a frameshift, resulting in a truncated protein core. The cartilage matrix from these patients stained poorly with antibody specific for perlecan, but there was staining of intracellular inclusion bodies. Biochemically, truncated perlecan was not secreted by the patient fibroblasts, but was degraded to smaller fragments within the cells. Thus, DDSH is caused by a functional null mutation of HSPG2. Our findings demonstrate the critical role of perlecan in cartilage development.