Autozygosity mapping of methylmalonic acidemia associated genes by short tandem repeat markers facilitates the identification of five novel mutations in an Iranian patient cohort
- 93 Downloads
Isolated Methylmalonic acidemia/aciduria (MMA) is a group of inborn errors of metabolism disease which is caused by defect in methylmalonyl-CoA mutase (MCM) enzyme. The enzyme has a key function in the catabolism of branched chain amino acids (BCAA, isoleucine, and valine), methionine, and threonine. MCM is encoded by a single gene named “MUT”. Other subtypes of MMA are caused by mutations in cblA (encoded by MMAA) and cblB (encoded by MMAB), which is involved in the synthesis of methylmalonyl–coenzyme A cofactor. Different types of mutations have been identified as the cause of MMA. However, the mutation spectrum of MMA in Iran has not been studied so far. Here, we aimed to investigate the MMA causative mutations in the Iranian population. Using STR (Short Tandem Repeat) markers, we performed autozygosity mapping to identify the potential pathogenic variants in 11 patients with clinical diagnosis of MMA. Nineteen STR markers which are linked to the MUT, MMAA and MMAB genes (the genes with known causative mutations in MMA) were selected for PCR-amplification using two recently designed multiplex PCR panels. Next, the families that were diagnosed with homozygous haplotypes for the candidate genes were directly sequenced. Five novel mutations (c.805delG, c.693delC, c.223A > T, c.668A > G and c.976A > G in MUT) were identified beside other 4 recurrent mutations (c.361insT in MUT, c.571C > T and c.197–1 G > T in MMAB and c.1075C > T in MMAA). In silico analyses were also performed to predict the pathogenicity of the identified variants. The mutation c.571C > T in MMAB was the most common mutation in our study.
KeywordsMethylmalonic acidemia (MMA) Autozygosity mapping Mutation analysis Iran
Compliance with ethical standards
Conflict of interest
There is no conflict of interest to declare.
Informed consent was received from 11 patients for participation in this study.
This study does not contain any animal study.
- Acquaviva C, Benoist JF, Pereira S, Callebaut I, Koskas T, Porquet D, Elion J (2005) Molecular basis of methylmalonyl-CoA mutase apoenzyme defect in 40 European patients affected by mut(o) and mut- forms of methylmalonic acidemia: identification of 29 novel mutations in the MUT gene. Hum Mutat 25(2):167–176CrossRefPubMedGoogle Scholar
- Jorge-Finnigan A, Aguado C, Sánchez-Alcudia R, Abia D, Richard E, Merinero B, Gámez A, Banerjee R, Desviat LR, Ugarte M, Pérez B (2010) Functional and structural analysis of five mutations identified in methylmalonic aciduria cblB type. Hum Mutat 31(9):1033–1042CrossRefPubMedPubMedCentralGoogle Scholar
- Lerner-Ellis JP, Gradinger AB, Watkins D, Tirone JC, Villeneuve A, Dobson CM, Montpetit A, Lepage P, Gravel RA, Rosenblatt DS (2006) Mutation and biochemical analysis of patients belonging to the cblB complementation class of vitamin B12-dependent methylmalonic aciduria. Mol Genet Metab 87(3):219–225CrossRefPubMedGoogle Scholar
- Manoli I, Sloan JL, and Venditti CP, Isolated Methylmalonic Acidemia, in GeneReviews((R)), Adam MP, et al., Editors. (1993) University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington. Seattle: Seattle WAGoogle Scholar