MUTATIONS IN ORTHOLOGOUS GENES IN HUMAN SPONDYLOEPIMETAPHYSEAL DYSPLASIA AND THE BRACHYMORPHIC MOUSE

The osteochondrodysplasias are a genetically heterogeneous group of di sorders affecting skeletal development, linear growth and the maintena nce of cartilage and bone. We have studied a large inbred Pakistani fa mily with a distinct form of recessively inherited spondyloepimetaphys eal dysplasia (SEMD) and mapped a gene associated with this dwarfing c ondition to chromosome 10q23-24, a region syntenic with the locus for the brachymorphic mutation on mouse chromosome 19. We identified two o rthologous genes, ATPSK2 and Atpsk2, encoding novel ATP sulfurylase/AP S kinase orthologues in the respective regions of the human and mouse genomes, We characterized a nonsense mutation in ATPSK2 in the SEMD fa mily and a missense mutation in the region of Atpsk2 encoding the APS kinase activity in the brachymorphic mouse. ATP sulfurylase/APS kinase catalyses the metabolic activation of inorganic sulfate to PAPS, the universal donor for post-translational protein sulfation in all cell t ypes. The cartilage-specificity of the human and mouse phenotypes prov ides further evidence of the critical role of sulfate activation in th e maturation of cartilage extracellular matrix molecules and the effec t of defects in this process on the architecture of cartilage and skel etogenesis.