Molecular and cellular mechanisms of congenital craniofacial disorders

Congenital skeletal abnormalities are a major part of birth defects. Among them, Cerebro-Costo-Mandibular syndrome (CCMS) is a rare congenital disorder comprising branchial arch-derived and thoracic skeletal malformations with striking rib-gaps. In the last two years our collaborators have conducted the largest clinical study of CCMS worldwide to provide accurate information about the diagnosis and prognosis for patients [1]. The genetic cause of CCMS was recently identified [2], involving mutations in the gene, SNRPB, encoding Small Nuclear Ribonucleoprotein-associated Protein B and B’ isoforms (SmB/B’). SmB/B’ are components of the major spliceosome, a dynamic macromolecule responsible for removing introns from almost every gene. Interestingly, an increasing number of craniofacial disorders are known to be caused by alterations in spliceosomal genes [3]. However, it is totally unknown how mutations in such fundamental genes can cause these specific phenotypes during embryogenesis, often affecting craniofacial development. This knowledge gap has prevented us from explaining the phenotypic and heredity variation, including non-penetrance that occurs in CCMS.
We will investigate the mechanism whereby such gene mutations result in specific developmental phenotypes. The approach is at molecular (DNA, mRNA and protein levels) and cellular levels using in vitro culture system. Chick embryos will also be used as an approachable model system.