Work on this project has focused on an autosomal recessive form of skeletal dysplasia, Cartilage Hair Hypoplasia (CHH) and the achondroplasia family of skeletal dysplasias. Cartilage hair hypoplasia has recently been found to be caused by mutations in the RNMP gene, which encodes an RNA that participates in the mitochondrial Ribonuclear Protein complex. Mutational analysis in Amish patients with CHH and non-Amish CHH patients is ongoing. The achondroplasia family of skeletal dysplasias includes three previously recognized diagnoses and one that has been defined under this project. The three well-established conditions are achondroplasia, hypochondroplasia and thanatophoric dysplasia (TD). Work published by our lab in the past described a new syndrome, Severe Achondroplasia with Developmental Delay and Acanthosis Nigricans (SADDAN). All four disorders in this family of conditions are caused by mutations in the gene encoding fibroblast growth factor receptor 3 (FGFR3). Work over the past two years has focused on the creation and characterization of two mouse models for FGFR3 disorders. Using a knock-in strategy, mice heterozygous for K644E and K644M mutations have been generated. Ongoing work is focused on creation of mice with K644N mutations, to model the human disorder hypochondroplasia. We are anticipating functional genomic and proteomic analysis of the nervous system and skeleton of these mice, in order to better understand the pathogenesis of these three disorders. Clinical efforts include examination of the causes of morbidity and mortality in achondroplasia, and description of previously uncharacterized skeletal dysplasias.
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