Structural and functional mutations of the perlecan gene cause Schwartz-Jampel syndrome, with myotonic myopathy and chondrodysplasia
Structural and functional mutations of the perlecan gene cause Schwartz-Jampel syndrome, with myotonic myopathy and chondrodysplasia
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DOI：
10.1086/340390
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发表时间：
2002-05-01
影响因子：
9.8
通讯作者：
Yamada, Y
中科院分区：
文献类型：
--
作者：
Arikawa-Hirasawa, E;Le, AH;Yamada, Y
Perlecan是一种大型硫酸肝素蛋白多糖，是基底膜和其他细胞外基质的组成部分，并与多种生物功能有关。perlecan基因（HSPG2）突变导致两类骨骼疾病：相对轻微的Schwartz-Jampel综合征（SJS）和严重的新生儿致命性节段性发育不良，Silverman-Handmaker型（DDSH）。SJS是一种常染色体隐性骨骼发育不良，以不同程度的肌强直和软骨发育不良为特征，SJS患者存活。SJS软骨营养不良性肌强直表型的分子机制尚不清楚。在本报告中，我们确定了五种不同的突变，导致三名不相关的SJS患者出现各种形式的perlecan。两例SJS患者的杂合突变要么产生缺乏V结构域的截短的perlecan，要么显著降低野生型perlecan的水平。第三名患者有一个纯合的7kb缺失，导致几乎全长的perlecan数量减少。与DDSH不同，SJS突变导致不同形式的perlecan水平降低，这些perlecan分泌到细胞外基质中，可能部分起作用。这些发现表明，perlecan在神经肌肉功能和软骨形成中起重要作用，并确定了DDSH和SJS表型严重程度差异的分子基础。
Perlecan, a large heparan sulfate proteoglycan, is a component of the basement membrane and other extracellular matrices and has been implicated in multiple biological functions. Mutations in the perlecan gene (HSPG2) cause two classes of skeletal disorders: the relatively mild Schwartz-Jampel syndrome (SJS) and severe neonatal lethal dyssegmental dysplasia, Silverman-Handmaker type (DDSH). SJS is an autosomal recessive skeletal dysplasia characterized by varying degrees of myotonia and chondrodysplasia, and patients with SJS survive. The molecular mechanism underlying the chondrodystrophic myotonia phenotype of SJS is unknown. In the present report, we identify five different mutations that resulted in various forms of perlecan in three unrelated patients with SJS. Heterozygous mutations in two patients with SJS either produced truncated perlecan that lacked domain V or significantly reduced levels of wild-type perlecan. The third patient had a homozygous 7-kb deletion that resulted in reduced amounts of nearly full-length perlecan. Unlike DDSH, the SJS mutations result in different forms of perlecan in reduced levels that are secreted to the extracellular matrix and are likely partially functional. These findings suggest that perlecan has an important role in neuromuscular function and cartilage formation, and they define the molecular basis involved in the difference in the phenotypic severity between DDSH and SJS.