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

Clinical Genetics
M StojiljkovicB Perez

Abstract

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 charact...Continue Reading

References

Aug 31, 2001·European Journal of Human Genetics : EJHG·C AcquavivaJ Elion
Feb 1, 2003·Molecular Genetics and Metabolism·B PérezM Ugarte
Oct 22, 2003·Molecular Genetics and Metabolism·Mary M NellisDean J Danner
Oct 7, 2004·Molecular Genetics and Metabolism·L R DesviatM Ugarte
Nov 4, 2004·Human Mutation·Jordan P Lerner-EllisDavid S Rosenblatt
Mar 23, 2005·Molecular Genetics and Metabolism·Maria Angeles MartínezBelén Pérez
Jun 21, 2006·Human Mutation·Pilar Rodríguez-PomboMagdalena Ugarte
Sep 11, 2014·Orphanet Journal of Rare Diseases·Matthias R BaumgartnerAnupam Chakrapani

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Citations

Nov 3, 2016·Current Opinion in Pediatrics·Jamie L Fraser, Charles P Venditti
Aug 28, 2020·American Journal of Human Genetics·Tamara S RomanJonathan S Berg

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