Pathogenic Homozygous Mutations in the DBT Gene (c.1174A>C) Result in Maple Syrup Urine Disease in a rs12021720 Carrier

Abstract

Objective Maple syrup urine disease (MSUD; OMIM #248600) is an autosomal recessive metabolic disorder in the catabolism of branched-chain amino acids (leucine, isoleucine, and valine) and may be lethal if untreated in affected newborns. Methods Single-nucleotide polymorphism haplotyping and Sanger sequencing of BCKDHA, BCKDHB, and DBT genes were performed in a cohort of 10 MSUD patients. Results We identified a 16.6 Mb homozygous region harboring the DBT gene in an Iranian girl presenting with MSUD. Sanger sequencing revealed a pathogenic homozygous variant (NM_001918.3: c.1174A > C) in the DBT gene. We further found a controversial variant (rs12021720: c.1150 A > G) in the DBT gene. This substitution (p.Ser384Gly) is highly debated in literature. Bioinformatics and cosegregation analysis, along with identifying the real pathogenic variants (c.1174 A > C), lead to terminate these various interpretations of c.1150 A > G variant. Conclusion Our study introduced c.1150 A > G as a polymorphic variant, which is informative for variant databases and also helpful in molecular diagnosis.

Pan-cancer analysis of the cuproptosis-related gene DBT that serves as an immunotherapy and prognostic biomarker

“…Dihydrolipoamide Branched Chain Transacylase E2(DBT) encodes the transacylase E2 subunit. A large number of studies have shown that mutations in DBT result in maple syrup urine disease type 2 (4,5), alternatively spliced transcript variants have been described(6, 7), but their biological validity has not been determined (5). Recently, it has been reported that DBT is one of the genes related to protein acylation in the process of cuproptosis(8).…”