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Dyssegmental dysplasia, Silverman-Handmaker type: Unexpected role of perlecan in cartilage development#


  • Eri Arikawa-Hirasawa,

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    • Eri Arikawa-Hirasawa, M.D., Ph.d., is a neurologist, who worked at the National Institute of Dental and Craniofacial Research, National Institutes of Health for the past 5 years. She is now an assistant professor in the Department of Neurology at Juntendo University Medical School in Japan. Her major interest has been in muscle disorders and neural development. She was instrumental in creating knockout mice for perlecan and identifying the unexpected cartilage defects in the mutant mice, whose phenotype led to the identification of mutations in the perlecan gene of DDSH patients.

  • William R. Wilcox,

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    • William R. Wilcox, M.D., PhD., is a Pediatrician and Medical Geneticist who has been on the faculty of Cedars-Sinai Medical Center in Los Angeles for 7 years. He is an Associate Professor of Pediatrics through the UCLA School of Medicine. His research interests include defining the clinical features, chondro-osseous morphology, and pathophysiology of the skeletal dysplasias and testing new treatments for inborn errors of metabolism.

  • Yoshihiko Yamada

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    • Building 30, Room 405, NIDCR, National Institutes of Health, 30 Convent Drive, Bethesda, Maryland 20892.
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    • Yoshihiko Yamada, Ph.D., is Chief of the Molecular Biology Section of the Craniofacial Developmental Biology and Regeneration Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health. His major interest has been in connective tissues, focusing especially on the structure and function of extracellular matrix (ECM) proteins and their gene regulation in development and diseases. He and his colleagues have cloned and characterized a number of ECM components, most of them for the first time in any species, including basement membrane proteins and cartilage matrix proteins.

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    This article was prepared by a group consisting of both United States Government employees and non-United States Government employees, and as such is subject to 117 U.S.C. Sec. 105.


Dyssegmental dysplasia, Silverman-Handmaker type (DDSH), is a lethal autosomal recessive form of dwarfism with characteristic anisospondylic micromelia. The remarkable similarities in the radiographic, clinical, and chondroosseous morphology of DDSH patients to those of perlecan-null mice led to the identification of mutations in the perlecan gene (HSPG2) of DDSH. Perlecan, a large heparan sulfate proteoglycan, is expressed in various tissues and is a component of all basement membrane extracellular matrices. A chondrodysplasia phenotype caused by the loss of perlecan was unexpected, because cartilage does not have basement membranes. Insertion and splicing mutations in HSPG2 of DDSH were found that were predicted to create a premature termination codon. Immunostaining and biochemical analysis revealed that the mutant perlecan molecules were unstable and not secreted into the extracellular matrix. These results indicate that DDSH is caused by functional null mutations of HSPG2 and that perlecan is essential for cartilage development. Published 2002 Wiley-Liss, Inc.