Grant: Project Grant

Most babies born with a congenital malformation die within the first year of life and although many mutations responsible for congenital syndromes have been identified the underlying mechanism responsible for these malformations remains under studied. We showed that heterozygous mutations in the core component of the spliceosome gene SNRPB are responsible for Cerebrocostomandibular Syndrome (CCMS). CCMS patients carry mutations that increase inclusion of a pretermination containing (PTC) exon (AE2) important for regulating Snrpb levels. These patients present with craniofacial and rib defects at birth and 50% die within the first month. Our goal is to uncover the requirement for SNRPB in the paraxial mesoderm, the precursor of the ribs and vertebrae. We generated several mutant mouse lines with mutation in Snrpb that develop abnormalities like those seen in CCMS. Using RNAseq we identified candidate genes important for ribs and vertebrae development. Our hypothesis is that reduced levels of RA, a vitamin A derivative, and mis-splicing of the chromatin modifier, Setd5, in presomitic mesoderm are responsible for vertebrae and rib defects in Snrpbtmx mutant embryos. We Aim to uncover the contribution of (1) increase levels of the RA catabolizing gene Cyp26a1 , and (2) reveal the contribution of mis-splicing of Setd5 to vertebral and rib defects in Snrpb mutant embryos; and (3) to evaluate the requirement of Snrpb in paraxial mesoderm for normal vertebrae and rib development. Our work will uncover pathways shared with other spliceosomopathies syndromes. Though a rare syndrome, rib and vertebrae abnormalities found in CCMS are also found in other poorly studied congenital malformations. Our mechanistic work will help in the development of treatments that can prevent or reduce the incidence of these defects in the population