**9. Growth differentiation factor-5 (***GDF-5***)**

Hotten *et al*. [9] determined that the *GDF5* gene contains two exons. Miyamoto *et al*. [113] reported that the gene encoding growth differentiation factor-5 (*GDF-5*) is associated with Osteoarthritis in Asian populations. An SNP in the 5′ untranslated region (UTR) of *GDF-5* showed significant association with hip osteoarthritis in 2 independent Japanese populations. This association was replicated for knee osteoarthritis in Japanese and Han Chinese populations. This SNP, located in the *GDF-5* core promoter, exert allelic differences on transcriptional activity in chondrogenic cells, with the susceptibility allele showing reduced activity. The findings implicated *GDF-5* as a susceptibility gene for Osteoarthritis and suggested that decreased *GDF-5* expression is involved in the pathogenesis of Osteoarthritis. [2] also isolated and characterized human *GDF5,* which they designated *CDMP1*, as well as human *GDF6 (CDMP2*). *GDF6* is predominantly expressed at sites of skeletal morphogenesis. Al-Yahyaee *et al*. [114–117] identified two mutations in the *GDF5* gene: a silent 1137A-G transition encoding lysine and a 1-bp deletion, 1144delG, predicting a frame shift resulting in loss of the biologically active C terminus of the protein. Thomas *et al*. [118] found that heterozygotes for the C400Y mutation had phenotypes resembling brachydactyly types A1, A4, or C.
