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

Eri Arikawa-Hirasawa, Alexander H. Le, Ichizo Nishino, Ikuya Nonaka, Nicola C. Ho, Clair A. Francomano, Prasanthi Govindraj, John R. Hassell, Joseph M. Devaney, Jürgen Spranger, Roger E. Stevenson, Susan Iannaccone, Marinos C. Dalakas, Yoshihiko Yamada

Research output: Contribution to journalArticle

118 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1368-1375
Number of pages8
JournalAmerican Journal of Human Genetics
Volume70
Issue number5
DOIs
StatePublished - 2002

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Myotonic Disorders
Enchondromatosis
Osteochondrodysplasias
Mutation
Genes
Extracellular Matrix
Myotonia
Heparan Sulfate Proteoglycans
perlecan
Basement Membrane
Cartilage
Phenotype

ASJC Scopus subject areas

  • Genetics

Cite this

Arikawa-Hirasawa, E., Le, A. H., Nishino, I., Nonaka, I., Ho, N. C., Francomano, C. A., ... Yamada, Y. (2002). Structural and functional mutations of the perlecan gene cause Schwartz-Jampel syndrome, with myotonic myopathy and chondrodysplasia. American Journal of Human Genetics, 70(5), 1368-1375. https://doi.org/10.1086/340390

Structural and functional mutations of the perlecan gene cause Schwartz-Jampel syndrome, with myotonic myopathy and chondrodysplasia. / Arikawa-Hirasawa, Eri; Le, Alexander H.; Nishino, Ichizo; Nonaka, Ikuya; Ho, Nicola C.; Francomano, Clair A.; Govindraj, Prasanthi; Hassell, John R.; Devaney, Joseph M.; Spranger, Jürgen; Stevenson, Roger E.; Iannaccone, Susan; Dalakas, Marinos C.; Yamada, Yoshihiko.

In: American Journal of Human Genetics, Vol. 70, No. 5, 2002, p. 1368-1375.

Research output: Contribution to journalArticle

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 2002, 'Structural and functional mutations of the perlecan gene cause Schwartz-Jampel syndrome, with myotonic myopathy and chondrodysplasia', American Journal of Human Genetics, vol. 70, no. 5, pp. 1368-1375. https://doi.org/10.1086/340390
Arikawa-Hirasawa, Eri ; Le, Alexander H. ; Nishino, Ichizo ; Nonaka, Ikuya ; Ho, Nicola C. ; Francomano, Clair A. ; Govindraj, Prasanthi ; Hassell, John R. ; Devaney, Joseph M. ; Spranger, Jürgen ; Stevenson, Roger E. ; Iannaccone, Susan ; Dalakas, Marinos C. ; Yamada, Yoshihiko. / Structural and functional mutations of the perlecan gene cause Schwartz-Jampel syndrome, with myotonic myopathy and chondrodysplasia. In: American Journal of Human Genetics. 2002 ; Vol. 70, No. 5. pp. 1368-1375.
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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

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