Molecular basis of cblX syndrome

National Institute Of Allergy And Infectious Diseases

Investigators

Abstract

Mutations in enzymes of the Vitamin B12/cobalamin metabolism or transport pathways can result in clinical phenotypes that include biochemical (methylmalonic aciduria, homocystinuria) and neurological presentations. A related syndrome, cblX, is characterized by a reduction of expression of a critical enzyme (MMACHC) in the cobalamin pathway and has been linked to mutations in the cellular transcriptional coactivator HCF-1. Similar to other cobalamin metabolism syndromes, CblX patients have a combination of severe developmental, biochemical, and neurological phenotypes (intellectual disability, epilepsy). However the full impacts of mutations in this coactivator and the molecular basis of cblX syndrome have not been investigated. In fiscal year 2019, a series of studies were undertaken to investigate the impacts of HCF-1 cblX mutations on the cellular transcriptome and HCF-1 occupancy at specific sites in the human genome using fibroblasts from cblX patients and cells/tissues from mouse models with the appropriate matching HCF-1 point mutations.