Mutation analysis of genes related to methylmalonic acidemia: identification of eight novel mutations
Methylmalonic acidemia (MMA), an inherited metabolic disease, results from genetic defects in methylmalonyl-CoA mutase or any of the proteins involved in adenosylcobalamin synthesis. This enzyme is classified into several complementation groups and genotypic classes. In this work we explain the biochemical, structural and genetic analysis of 25 MMA patients, from Iran. The diagnosis was established by the measurement of propionylcarnitine in blood using tandem mass spectrometry and confirmed using a gas chromatography–flame ionization detector. Using clinical, biochemical, structural and molecular analyses we identified 15 mut MMA, three cblA, one cblB, and four cblC-deficient patients. Among mutations identified in the MUT gene (MUT) only one, the c.1874A>C (p.D625A) variant, is likely a mut− mutation. The remaining mutations are probably mut0. Here, we present the first molecular analysis of MMA in Iranian patients and have identified eight novel mutations. Four novel mutations (p.D625A, p.R326G, p.V157F, p.F379L) were seen exclusively in patients from northern Iran. One novel splice site mutation (c.2125-3C>G) in MUT and two novel mutation (p.N225M and p.A99P) in the MMAA gene were associated with patients from eastern Iran. The rs184829210 SNP was recognized only in patients with the novel c.958G>A (p.A320T) mutation. This study confirms pathogenesis of deficient enzyme activity in MUT, MMAA, MMAB, and MMACHC as previous observations. These results could act as a basis for the performance of pharmacological therapies for increasing the activity of proteins derived from these mutations.
KeywordsMutation analysis MUT MMAA MMAB MMACHC Biochemical analysis Novel mutation Methylmalonic acidemia Iranian population
Gas chromatography–flame ionization detector
Human gene mutation database
Maple syrup urine disease
Mashhad University of Medical Sciences
Reverse transcriptase-polymerase chain reaction
Single nucleotide polymorphism
This research was supported and funded by the Immunology Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
Compliance with ethical standards
Conflict of interest
All authors declare they have no conflicts of interest.
- 4.Rosenblatt DS, Fenton WA (2001) Inherited disorders of folate and cobalamin transport and metabolism. In: Scriver CR, Beaudet AL, Valle D, Sly WS (eds) The metabolic and molecular bases of inherited disease. McGraw-Hill, New York, pp 3897–3933Google Scholar
- 11.Han L, Gao X, Ye J, Qiu W, Gu X (2005) Application of tandem mass spectrometry in diagnosis of organic acidemias. Chin J Pediatr 43:325–330Google Scholar