AN ALPHA-1(II) GLY(913) TO CYS SUBSTITUTION PREVENTS THE MATRIX INCORPORATION OF TYPE-II COLLAGEN WHICH IS REPLACED WITH TYPE-I AND TYPE-III COLLAGENS IN CARTILAGE FROM A PATIENT WITH HYPOCHONDROGENESIS

A heterozygous mutation in the COL2A1 gene was identified in a patient with hypochondrogenesis. The mutation was a single nucleotide transit ion of G3285T that resulted in an amino acid substitution of Cys for G ly(913) in the alpha 1(II) chain of type II collagen, This amino acid change disrupted the obligatory Gly-X-Y triplet motif required for the normal formation of a stable collagen triple helix and prevented the deposition of type II collagen into the proposita's cartilage, which c ontained predominantly type I and III collagens and minor amounts of t ype XI collagen. Biosynthetic analysis of collagens produced and secre ted by the patient's chondrocytes cultured in alginate beads was consi stent with the in vivo matrix composition, demonstrating that the main products were type I and III collagens, along with type XI collagen, The synthesis of the cartilage-specific type XI collagen at similar le vels to controls indicated that the isolated cartilage cells had re-di fferentiated to the chondrocyte phenotype, The chondrocytes also produ ced small amounts of type II collagen, but this was post-translational ly overmodified and not secreted. These data further delineate the bio chemical and phenotypic consequences of mutations in the COL2A1 gene a nd suggest that cartilage formation and bone development can take plac e in the absence of type II collagen. (C) 1996 Wiley-Liss, Inc.