TY - JOUR
T1 - Structural and functional mutations of the perlecan gene cause Schwartz-Jampel syndrome, with myotonic myopathy and chondrodysplasia
AU - Arikawa-Hirasawa, Eri
AU - Le, Alexander H.
AU - Nishino, Ichizo
AU - Nonaka, Ikuya
AU - Ho, Nicola C.
AU - Francomano, Clair A.
AU - Govindraj, Prasanthi
AU - Hassell, John R.
AU - Devaney, Joseph M.
AU - Spranger, Jürgen
AU - Stevenson, Roger E.
AU - Iannaccone, Susan
AU - Dalakas, Marinos C.
AU - Yamada, Yoshihiko
N1 - Funding Information:
We thank Drs. C. McDonald, W. Fowler, E. Hoffman, C. Schwartz, and W. Wilcox, for helpful discussions, and Drs. R. Rotundo and H. Kleinman, for comments on the manuscript. We also thank H. Grant, for editorial help, and R. Granger, for technical help. This work was supported by National Institutes of Health intramural funds to Y.Y., C.F., and M.D. and by grants to J.R.H. from the Shriners of North America. A.H.L. is a Howard Hughes Medical Institute–National Institutes Research Fellow.
PY - 2002
Y1 - 2002
N2 - 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.
AB - 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.
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U2 - 10.1086/340390
DO - 10.1086/340390
M3 - Article
C2 - 11941538
AN - SCOPUS:18344383853
SN - 0002-9297
VL - 70
SP - 1368
EP - 1375
JO - American journal of human genetics
JF - American journal of human genetics
IS - 5
ER -