title: Molecular genetic analysis of MSUD from India reveals mutations causing altered protein truncation affecting the C-termini of E1α and E1β.
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.
authors.affiliation: Laboratory of Molecular Oncology, Centre for DNA Fingerprinting and Diagnostics, Hyderabad, India. bashyam@cdfd.org.in
authors.forename: Murali D
authors.initials: MD
authors.lastname: Bashyam
authors.forename: Ajay K
authors.initials: AK
authors.lastname: Chaudhary
authors.forename: Manjari
authors.initials: M
authors.lastname: Sinha
authors.forename: H A
authors.initials: HA
authors.lastname: Nagarajaram
authors.forename: A Radha Rama
authors.initials: AR
authors.lastname: Devi
authors.forename: Leena
authors.initials: L
authors.lastname: Bashyam
authors.forename: E Chandrakanth
authors.initials: EC
authors.lastname: Reddy
authors.forename: Ashwin
authors.initials: A
authors.lastname: Dalal
mesh_terms: D020413:3' Untranslated Regions; D042942:3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide) / Q000737:chemistry* / Q000235:genetics; D000595:Amino Acid Sequence; D000596:Amino Acids / Q000737:chemistry; D001483:Base Sequence; D018389:Codon, Nonsense / Q000737:chemistry / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D005820:Genetic Testing; D015894:Genome, Human; D005838:Genotype; D006801:Humans; D007194:India; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008375:Maple Syrup Urine Disease / Q000175:diagnosis / Q000235:genetics*; D008969:Molecular Sequence Data; D009097:Multienzyme Complexes / Q000737:chemistry* / Q000235:genetics; D020125:Mutation, Missense; D020871:RNA Stability; D016415:Sequence Alignment; D020539:Sequence Analysis, Protein; D017384:Sequence Deletion
chemical_list: D020413:3' Untranslated Regions; D000596:Amino Acids; D018389:Codon, Nonsense; D009097:Multienzyme Complexes; D042942:3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)