Developmental and molecular basis for a craniofacial metabolic syndrome

Project Summary
While causal genetic variants have been identified for many craniofacial syndromes, the functions of these genes
in normal development and the mechanisms by which these variants lead to disease often remain unknown.
Catel-Manzke syndrome (CMS) is a condition in which patients exhibit Pierre Robin Sequence (PRS),
encompassing micrognathia and cleft secondary palate, together with limb and cardiovascular phenotypes and
is caused by mutations in the dTDP-D-Glucose 4,6-dehydratase (TGDS)-encoding gene. The developmental
and molecular functions of TGDS are unknown but our preliminary data indicate it may function in pathways
impacting glycosaminoglycan metabolism. We have used next-generation CRISPR/Cas9 gene-editing
approaches in mice to generate an allelic series that models CMS and enables the study of Tgds function in
vivo. We propose a series of mouse genetic and quantitative morphometric assays to pinpoint the affected
developmental processes, which we combine with unbiased transcriptomic, glycomic, and metabolomic
approaches to build a foundation for understanding CMS etiology and Tgds developmental function. Completion
of these studies will provide novel insights into the function of an unstudied gene, reveal the etiology of a
craniofacial syndrome, and contribute to our fundamental understanding of how metabolic pathways regulate
craniofacial development.

Grant Number: 1R21DE033889-01A1
NIH Institute/Center: NIH
Principal Investigator: Jeffrey Bush