A COL2A1 MUTATION IN ACHONDROGENESIS TYPE-II RESULTS IN THE REPLACEMENT OF TYPE-II COLLAGES BY TYPE-I AND TYPE-III COLLAGENS IN CARTILAGE

An autosomal dominant mutation in the COL2A1 gene was identified in a fetus with achondrogenesis type II, A transition of G(2853) to A in ex on 41 produced a substitution of Gly(769) by Ser within the triple hel ical domain of the alpha 1(II) chain of type II collagen, interrupting the mandatory Gly-X-Y triplet sequence required for the normal format ion of stable triple helical type II collagen molecules, resulting in the complete absence of type II collagen in the cartilage, which had a gelatinous composition, Type I and III collagens were the major speci es found in cartilage tissue and synthesized by cultured chondrocytes along with cartilage type XI collagen, However, cultured chondrocytes produced a trace amount of type II collagen, which was retained within the cells and not secreted, In situ hybridization of cartilage sectio ns showed that the chondrocytes produced both type II and type I colla gen mRNA, As a result, it is likely that the chondrocytes produced typ e II collagen molecules, which were then degraded. The close proximity of the Gly(769) substitution by Ser to the mammalian collagenase clea vage site at Gly(775)-Leu(776) may have produced an unstable domain th at was highly susceptible to proteolysis, The type I and III collagens that replaced type II collagen were unable to maintain the normal str ucture of the hyaline cartilage but did support chondrocyte maturation , evidenced by the expression of type X collagen in the hypertrophic z one of the growth plate cartilage.