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 2025, mouse models representing two distinct HCF-1 cblX mutations were used to identify alterations in cellular transcription in multiple tissues relevant to cblX patient phenotypes. These data sets demonstrated that HCF-1 cblX mutations result in multiple biochemical disorders as well as misregulation of specific pathways that could contribute to cblX syndrome.