Phenotypic variation in the etiology and pathogenesis of congenital craniofacial birth defects such as Treacher Collins syndrome

Abstract

Neural crest cells gives rise to the majority of the bone, cartilage, connective and peripheral nerve tissues in the head and face. Craniofacial anomalies which account for approximately one third of all congenital birth defects arise largely through defects in neural crest cell patterning. Treacher Collins Syndrome (TCS) is a rare human congenital disorder of craniofacial development, characterised by developmental anomalies including hypoplasia of the facial bones, middle and external ear defects and cleft palate. TCS is associated with mutations in the TCOF1 gene which encodes a nucleolar protein known as treacle. More than 100 family specific mutations have been identified however there is no genotype‐phenotype correlation. We have characterised mouse models of Treacher Collins Syndrome via null mutation of Tcof1 which exhibit differing severity and penetrance on DBA and C57Bl/6 backgrounds. We are currently exploring spatiotemporal activity, endogenous levels and background specific modifiers as regulators of the etiology and pathogenesis of craniofacial malformations syndromes such as TCS.