Mutations in the heparan-sulfate proteoglycan glypican 6 (GPC6) impair endochondral ossification and cause recessive omodysplasia.
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.
Campos-Xavier
Ana Belinda
AB
Division of Molecular Pediatrics, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
Martinet
Danielle
D
Bateman
John
J
Belluoccio
Dan
D
Rowley
Lynn
L
Tan
Tiong Yang
TY
Baxová
Alica
A
Gustavson
Karl-Henrik
KH
Borochowitz
Zvi U
ZU
Innes
A Micheil
AM
Unger
Sheila
S
Beckmann
Jacques S
JS
Mittaz
Lauréane
L
Ballhausen
Diana
D
Superti-Furga
Andrea
A
Savarirayan
Ravi
R
Bonafé
Luisa
L
D000015:Abnormalities, Multiple / Q000235:genetics*; D000818:Animals; D002675:Child, Preschool; D019902:Chondrocytes / Q000378:metabolism*; D002874:Chromosome Mapping; D002882:Chromosomes, Human, Pair 13 / Q000235:genetics; D055028:Comparative Genomic Hybridization; D004392:Dwarfism / Q000235:genetics*; D005260:Female; D005455:Fluorescent Antibody Technique; D005808:Genes, Recessive / Q000235:genetics*; D053673:Glypicans / Q000235:genetics*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D051379:Mice; D009154:Mutation / Q000235:genetics*; D010012:Osteogenesis / Q000502:physiology*
C120300:GPC6 protein, human; D053673:Glypicans