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Dyssegmental dysplasia, Silverman-Handmaker type, is caused by functional null mutations of the perlecan gene

Nature Genetics volume 27, pages 431–434 (2001)Cite this article

Abstract

Perlecan is a large heparan sulfate (HS) proteoglycan present in all basement membranes and in some other tissues such as cartilage1,2, and is implicated in cell growth and differentiation3,4,5. Mice lacking the perlecan gene6,7 (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.

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Figure 1: Radiographic and histologic features of DDSH and the perlecan-null mouse.
Figure 2: Immunostaining of the resting zone of cartilage with a monoclonal antibody to perlecan protein core domain III.
Figure 3: Immunostaining of cultured fibroblasts.
Figure 4: Biochemical analysis of proteoglycans manufactured by cultured fibroblasts.
Figure 5: Mutation analysis.

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Acknowledgements

We thank D. Rimoin, R. Lachman, E. Cukierman, E. Hoffman, C. Francomano, N. Ho, H. Watanabe, K. Kimata and H. Grand for comments; W. Cohen and J. King for referring the cases to the International Skeletal Dysplasia Registry; K. Yamada for anti-fibronectin antibodies; J. Couchman and R. Timpl for anti-perlecan antibodies; and B. Mekikian, K. Bolland and N. Hayes for technical support. W.R.W. was supported by NIH 5P01 HD22657. Some of this work was supported by grants from Seikagaku Corporation and from the Shriners of North America.

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Authors and Affiliations

  1. Craniofacial Developmental Biology and Regeneration Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, USA

    Eri Arikawa-Hirasawa, Alexander H. Le & Yoshihiko Yamada

  2. Medical Genetics Birth Defects Center, Steven Spielberg Pediatric Research Center, Cedars-Sinai Burns and Allen Research Institute,

    William R. Wilcox

  3. Department of Pediatrics, UCLA School of Medicine, Los Angeles, California, USA

    William R. Wilcox

  4. Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, Department of Obstetrics and Gynecology, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, California, USA

    Neil Silverman

  5. Shriners Hospital for Children, Tampa, Florida, USA

    Prasanthi Govindraj & John R. Hassell

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Correspondence to Yoshihiko Yamada.

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Arikawa-Hirasawa, E., Wilcox, W., Le, A. et al. Dyssegmental dysplasia, Silverman-Handmaker type, is caused by functional null mutations of the perlecan gene. Nat Genet 27, 431–434 (2001). https://doi.org/10.1038/86941

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