We study the molecular basis of human genetic disorders and genotype/phenotype pathways. Our principle models are mutations in human collagen genes and genes that encode the protein chaperones and other modifying proteins. Although most mutations in the collagen genes produce phenotypes when one allele is altered (dominant inheritance) we have identified mutations in five additional genes that act in the post-translational modification pathway, chain assembly, and regulate the transition from the ER to Golgi and then further along the pathway. These genes (PPIB, CRTAP, LEPRE1, SERPINH1, FKBP10), which encode prolyl cis-trans isomerases, hydroxylases, and chaperones, affect the assembly of chains, the folding of the triple helix of collagens, and influence secretion. We are examining the precise mechanisms by which mutations induce the phenotypes and are determining the details of protein modification, assembly and interactions. These genes do not complete the list of genes that give rise to phenotypes we study so we are looking by linkage and, shortly, full exome sequencing. To understand details of molecular pathogenesis, we are examining the pathways altered by these mutations. Finally, we are studying parental mosaicism for dominant disorders, and how the order of mRNA splicing influences the outcome of splice site mutations
