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, nail-patella syndrome, Ellis-van Crevald (EvC) syndrome, Brachydactyly type C, Schmid metaphyseal chondrodysplasia (SMCD), and the type II collagen disorders. Pycnodysostosis - We used linkage analysis to narrow the region of the pycnodysostosis locus to 3cM. Using a positional candidate gene approach, the gene encoding extracellular matrix protein 1 (ECM1) and cathepsin K were analyzed. We have identified cathepsin K as the pycnodysostosis gene. Ellis-van Crevald syndrome - Together with M. Polymeropoulos (LGDR), we have narrowed the region of the EvC gene to roughly 1 cM on chromosome 4p. We have also excluded HOX7 as the EvC gene. Brachydactyly type C was mapped to human chromosome 12 in collaboration with Mihaelis Polymeropoulos, LGDR, NCHGR. Nail-Patella syndrome - Linkage mapping has narrowed the candidate region for the NPS locus to a 1-2 cM interval between markers D9S60 and the adenylate kinase gene on 9q34. SMCD - Three new families have been ascertained. In one family, segregation of a previously unreported nonsense mutation in the NC1 domain of COL10A1 was demonstrated with the SMCD phenotype. In a second family. a tyrosine to histidine mutation in type X collagen has been identified in the proband but co-segregation remains to be proved. In the third family, no mutation has yet to be identified. Type II collagen disorders - We have identified 4 new mutations in individuals with Kniest dysplasia, all of which result in shortened type II collagen fibers. These mutations are all clustered between exons 12 and 24, further adding to the hypothesis that mutations of distinct type and location result in the Kniest phenotype. We have also further clinically and molecularly defined Stickler syndrome families, suggesting the presence of a fourth Stickler gene, and suggesting that the complication of severe visual manifestations may distinguish between families linked to COL2A1 and those due to mutations in other genes.
