Mutations in the Heparan-Sulfate Proteoglycan Glypican 6 (GPC6
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- 作者：Ana Belinda Campos-Xavier ; Danielle Martinet ; John Bateman ; Dan Belluoccio ; Lynn Rowley ; Tiong Yang Tan ; Alica Baxová ; Karl-Henrik Gustavson ; Zvi U. Borochowitz ; A. Micheil Innes ; Sheila Unger ; Jacques S. Beckmann ; Lauré ; ane Mittaz ; Diana Ballhausen ; Andrea Superti-Furga ; Ravi Savarirayan
- 刊名：The American Journal of Human Genetics
- 出版年：2009
- 出版时间：12 June 2009
- 年：2009
- 卷：84
- 期：6
- 页码：760-770
- 全文大小：1193 K
文摘
Glypicans are a family of glycosylphosphatidylinositol (GPI)-anchored, membrane-bound heparan sulfate (HS) proteoglycans. Their biological roles are only partly understood, although it is assumed that they modulate the activity of HS-binding growth factors. The involvement of glypicans in developmental morphogenesis and growth regulation has been highlighted by Drosophila mutants and by a human overgrowth syndrome with multiple malformations caused by glypican 3 mutations (Simpson-Golabi-Behmel syndrome). We now report that autosomal-recessive omodysplasia, a genetic condition characterized by short-limbed short stature, craniofacial dysmorphism, and variable developmental delay, maps to chromosome 13 (13q31.1-q32.2) and is caused by point mutations or by larger genomic rearrangements in glypican 6 (GPC6). All mutations cause truncation of the GPC6 protein and abolish both the HS-binding site and the GPI-bearing membrane-associated domain, and thus loss of function is predicted. Expression studies in microdissected mouse growth plate revealed expression of Gpc6 in proliferative chondrocytes. Thus, GPC6 seems to have a previously unsuspected role in endochondral ossification and skeletal growth, and its functional abrogation results in a short-limb phenotype.