This study is to identify disease genes causing a variety of human skeletal dysplasias, and to identify relationships between the identified mutations and the resulting phenotypes. Disorders studied include, but are not limited to, pycnodysostosis, Ellis-van Crevald (EvC) syndrome, Brachydactyly type C and the type II collagen disorders. Pycnodysostosis -continuing studies include analysis of cathepsin K activity in the macrophage from affected patients, as well as molecular analysis of the cathepsin K gene for new mutations. Ellis-van Crevald syndrome. On going studies, in collaboration with M. Polymeropoulos and M. Burn, include exon trapping in the EvC candidate interval, positional candidate gene analysis, and cDNA selection studies. Brachydactyly type C. Further linkage studies and positional candidate gene analysis are in progress for this phenotype. Type II collagen disordera. We used heteroduplex analysis to identify sequence anomalies in 4 individuals with Kniest dysplasia. Sequencing of the probands' genomic DNA identified three new dominant mutations in COL2A1 which result in Kniest dysplasia: a 21bp deletion in exon 16, a 18 bp deletion in exon 19, and 4 bp deletions in the splice donor sites of introns 14 and 20. A previously described Kniest mutation was identified in a fourth proband. This mutation was a 28bp deletion at the COL2A1 exon 12/intron 12 junction, deleting the splice donor site. These data suggest that Kniest dysplasia predominately results from shorter type II collagen monomers, and support the hypothesis that alteration of a domain, which may span from COL2A1 exons 12-24, leads to the Kniest phenotype.
