Molecular and phenotypic characteristics of seven novel mutations causing branched-chain organic acidurias

Clin Genet. 2016 Sep;90(3):252-7. doi: 10.1111/cge.12751. Epub 2016 Mar 4.


Specific mitochondrial enzymatic deficiencies in the catabolism of branched-chain amino acids cause methylmalonic aciduria (MMA), propionic acidemia (PA) and maple syrup urine disease (MSUD). Disease-causing mutations were identified in nine unrelated branched-chain organic acidurias (BCOA) patients. We detected eight previously described mutations: p.Asn219Tyr, p.Arg369His p.Val553Glyfs*17 in MUT, p.Thr198Serfs*6 in MMAA, p.Ile144_Leu181del in PCCB, p.Gly288Valfs*11, p.Tyr438Asn in BCKDHA and p.Ala137Val in BCKDHB gene. Interestingly, we identified seven novel genetic variants: p.Leu549Pro, p.Glu564*, p.Leu641Pro in MUT, p.Tyr206Cys in PCCB, p.His194Arg, p.Val298Met in BCKDHA and p.Glu286_Met290del in BCKDHB gene. In silico and/or eukaryotic expression studies confirmed pathogenic effect of all novel genetic variants. Aberrant enzymes p.Leu549Pro MUT, p.Leu641Pro MUT and p.Tyr206Cys PCCB did not show residual activity in activity assays. In addition, activity of MUT enzymes was not rescued in the presence of vitamin B12 precursor in vitro which was in accordance with non-responsiveness or partial responsiveness of patients to vitamin B12 therapy. Our study brings the first molecular genetic data and detailed phenotypic characteristics for MMA, PA and MSUD patients for Serbia and the whole South-Eastern European region. Therefore, our study contributes to the better understanding of molecular landscape of BCOA in Europe and to general knowledge on genotype-phenotype correlation for these rare diseases.

Keywords: activity assay; genotype-phenotype correlation; maple syrup urine disease; methylmalonic aciduria; mutations; propionic acidemia.

MeSH terms

  • 3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide) / chemistry
  • 3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide) / genetics*
  • Amino Acid Metabolism, Inborn Errors / genetics*
  • Amino Acid Metabolism, Inborn Errors / physiopathology
  • Amino Acids, Branched-Chain / genetics
  • Female
  • Genotype
  • Humans
  • Infant
  • Infant, Newborn
  • Male
  • Maple Syrup Urine Disease / genetics*
  • Maple Syrup Urine Disease / physiopathology
  • Methylmalonyl-CoA Decarboxylase / chemistry
  • Methylmalonyl-CoA Decarboxylase / genetics*
  • Mitochondrial Membrane Transport Proteins / chemistry
  • Mitochondrial Membrane Transport Proteins / genetics*
  • Mutation
  • Phenotype
  • Propionic Acidemia / genetics*
  • Propionic Acidemia / physiopathology
  • Protein Conformation


  • Amino Acids, Branched-Chain
  • MMAA protein, human
  • Mitochondrial Membrane Transport Proteins
  • 3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)
  • Methylmalonyl-CoA Decarboxylase

Supplementary concepts

  • Methylmalonic acidemia