RET effects in Hirschsprung disease
Learning the Rules of Complex Human Disease
Like most complex human diseases, Hirschsprung disease, the failure of enteric neural crest cell colonization of the gut, follows a genetic pattern of multi-factorial inheritance where sequence variants in multiple genes specify disease risk. Further, most of this risk arises from coding and regulatory variants in the gene encoding the tyrosine kinase receptor RET and its gene regulatory network (GRN). Many groups are attempting to saturate additional gene discovery by sequencing very large numbers of patients in order to find the rarest of variants. Our alternative approach is to use “Big-DNA” technology to engineer humanized mice, beginning with the highly characterized RET locus, to understand the genetic rules by which variants specify regulatory changes to alter gene expression and, in turn, affect cell behavior and the disease phenotype. These mice can then be cross-bred to variants in the RET GRN to ask which variant combinations in which genes cause clinical presentation of disease.
IN COLLABORATION WITH:
Ryan Fine, PhD, Center for Human Genetics and Genomics (CHGG)
Aravinda Chakravarti, Director of NYU Center for Human Genetics and Genomics (CHGG)
Funding:
National Institute of Child Health and Human Development (NICHD)