Structural and functional mutations of the perlecan gene cause Schwartz-Jampel syndrome, with myotonic myopathy and chondrodysplasia

被引:132
作者
Arikawa-Hirasawa, E
Le, AH
Nishino, I
Nonaka, I
Ho, NC
Francomano, CA
Govindraj, P
Hassell, JR
Devaney, JM
Spranger, J
Stevenson, RE
Iannaccone, S
Dalakas, MC
Yamada, Y
机构
[1] Natl Inst Dent & Craniofacial Res, Craniofacial Dev Biol & Regenerat Branch, Bethesda, MD USA
[2] NINCDS, Bethesda, MD 20892 USA
[3] Natl Inst Neurosci, Dept Ultrastruct Res, Tokyo, Japan
[4] NIA, Genet Lab, Baltimore, MD 21224 USA
[5] Johns Hopkins Bayview Med Ctr, Baltimore, MD USA
[6] Shriners Hosp Children, Tampa, FL USA
[7] Childrens Natl Med Ctr, Washington, DC 20010 USA
[8] Greenwood Genet Ctr, Greenwood, SC 29646 USA
[9] Texas Scottish Rite Hosp Children, Dallas, TX 75219 USA
基金
美国国家卫生研究院;
关键词
D O I
10.1086/340390
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
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.
引用
收藏
页码:1368 / 1375
页数:8
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