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

摘要: Perlecan is a large heparan sulfate (HS) proteoglycan present in all basement membranes and some other tissues such as cartilage1,2, implicated cell growth differentiation3,4,5. Mice lacking the perlecan gene6,7 (Hspg2) have severe chondrodysplasia with dyssegmental ossification of spine show radiographic, clinical chondro-osseous morphology similar to lethal autosomal recessive disorder humans termed dysplasia, Silverman-Handmaker type (DDSH; MIM 224410). Here we report homozygous, 89-bp duplication exon 34 HSPG2 pair siblings DDSH born consanguineous parents, heterozygous point mutations 5′ donor site intron 52 middle 73 third, unrelated patient, causing skipping entire exons transcript, respectively. These are predicted cause frameshift, resulting truncated protein core. The cartilage matrix from these patients stained poorly antibody specific for perlecan, but there was staining intracellular inclusion bodies. Biochemically, not secreted by patient fibroblasts, degraded smaller fragments within cells. Thus, caused functional null mutation HSPG2. Our findings demonstrate critical role development.