Molecular genetic analysis of MSUD from India reveals mutations causing altered protein truncation affecting the C-termini of E1α and E1β

Murali D. Bashyam*, Ajay K. Chaudhary, Manjari Sinha, H. A. Nagarajaram, A. Radha Rama Devi, Leena Bashyam, E. Chandrakanth Reddy, Ashwin Dalal

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

Maple Syrup Urine Disease is a rare metabolic disorder caused by reduced/absent activity of the branched chain α-Ketoacid dehydrogenase enzyme complex. Mutations in BCKDHA, BCKDHB, and DBT, that encode important subunits of the enzyme complex namely E1α, E1β, and E2, are the primary cause for the disease. We have performed the first molecular genetic analysis of MSUD from India on nine patients exhibiting classical MSUD symptoms. BCKDHA and BCKDHB mutations were identified in four and five patients, respectively including seven novel mutations namely the BCKDHA c.1249delC, c.1312T>C, and c.1561T>A and the BCKDHB c.401T>A, c.548G>A, c.964A>G, and c.1065delT. The BCKDHB c.970C>T (p.R324X) mutation was shown to trigger nonsense mediated decay-based degradation of the transcript. Seven of the total 11 mutations resulted in perturbations in the E1α or E1β C-termini either through altered termination or through an amino acid change; these are expected to result in disruption of E1 enzyme complex assembly. Our study has therefore revealed that BCKDHA and BCKDHB mutations might be primarily responsible for MSUD in the Indian population.

Original languageEnglish (US)
Pages (from-to)3122-3132
Number of pages11
JournalJournal of Cellular Biochemistry
Volume113
Issue number10
DOIs
StatePublished - Oct 1 2012

Keywords

  • BCKDHA
  • BCKDHB
  • MSUD
  • mutation
  • truncation

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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