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, E1ß, 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 E1ß 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.
Subject(s)
3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)/chemistry , Maple Syrup Urine Disease/genetics , Multienzyme Complexes/chemistry , Mutation, Missense , 3' Untranslated Regions , 3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)/genetics , Amino Acid Sequence , Amino Acids/chemistry , Base Sequence , Codon, Nonsense/chemistry , Codon, Nonsense/genetics , DNA Mutational Analysis , Female , Genetic Testing , Genome, Human , Genotype , Humans , India , Infant , Infant, Newborn , Male , Maple Syrup Urine Disease/diagnosis , Molecular Sequence Data , Multienzyme Complexes/genetics , RNA Stability , Sequence Alignment , Sequence Analysis, Protein , Sequence DeletionABSTRACT
Analysis of seven Indian phenylketonuria families has revealed four novel mutations in the phenylalanine hydroxylase gene; two affected consensus splice sequence and the 3' UTR, respectively, while the other two were single base insertion and deletion mutations, respectively. A novel 3' splice site mutation c.168-2A>G resulted in the activation of a cryptic 3' splice site that generated a premature termination codon leading to very low levels of the mutant transcript, probably due to activation of the nonsense-mediated decay (NMD) pathway. This is probably the first report of PKU caused by the activation of NMD.
