Abstract
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.
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References
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):167–176
Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, Kondrashov AS, Sunyaev SR (2010) A method and server for predicting damaging missense mutations. Nat Methods 7(4):248–249
Alkhunaizi AM, Al-Sannaa N (2017) Renal involvement in methylmalonic aciduria. Kidney Int Rep 2(5):956–960
Benson G (1999) Tandem repeats finder: a program to analyze DNA sequences. Nucleic Acids Res 27(2):573–580
Brasil S, Richard E, Jorge-Finnigan A, Leal F, Merinero B, Banerjee R, Desviat LR, Ugarte M, Pérez B (2015) Methylmalonic aciduria cblB type: characterization of two novel mutations and mitochondrial dysfunction studies. Clin Genet 87(6):576–581
Dempsey-Nunez L, Illson ML, Kent J, Huang Q, Brebner A, Watkins D, Gilfix BM, Wittwer CT, Rosenblatt DS (2012) High resolution melting analysis of the MMAA gene in patients with cblA and in those with undiagnosed methylmalonic aciduria. Mol Genet Metab 107(3):363–367
den Dunnen JT, Antonarakis SE (2000) Mutation nomenclature extensions and suggestions to describe complex mutations: a discussion. Hum Mutat 15(1):7–12
Dobson CM, Wai T, Leclerc D, Kadir H, Narang M, Lerner-Ellis JP, Hudson TJ, Rosenblatt DS, Gravel RA (2002) Identification of the gene responsible for the cblB complementation group of vitamin B12-dependent methylmalonic aciduria. Hum Mol Genet 11(26):3361–3369
Forny P, Schnellmann AS, Buerer C, Lutz S, Fowler B, Froese DS, Baumgartner MR (2016) Molecular genetic characterization of 151 Mut-type Methylmalonic Aciduria patients and identification of 41 novel mutations in MUT. Hum Mutat 37(8):745–754
Hamamy H (2012) Consanguineous marriages : preconception consultation in primary health care settings. J Community Genet 3(3):185–192
Han LS, Huang Z, Han F, Wang Y, Gong ZW, Gu XF (2017) Eight novel MUT loss-of-function missense mutations in Chinese patients with isolated methylmalonic academia. World J Pediatr 13(4):381–386
Harrington EA, Sloan JL, Manoli I, Chandler RJ, Schneider M, McGuire PJ, Calcedo R, Wilson JM, Venditti CP (2016) Neutralizing antibodies against adeno-associated viral capsids in patients with mut methylmalonic acidemia. Hum Gene Ther 27(5):345–353
Hauser NS, Manoli I, Graf JC, Sloan J, Venditti CP (2011) Variable dietary management of methylmalonic acidemia: metabolic and energetic correlations. Am J Clin Nutr 93(1):47–56
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):1033–1042
Keyfi F, Abbaszadegan MR, Rolfs A, Orolicki S, Moghaddassian M, Varasteh A (2016a) Identification of a novel deletion in the MMAA gene in two Iranian siblings with vitamin B12-responsive methylmalonic acidemia. Cell Mol Biol Lett 21:4
Keyfi F, Talebi S, Varasteh AR (2016b) Methylmalonic acidemia diagnosis by laboratory methods. Rep Biochem Mol Biol 5(1):1–14
Kumar P, Henikoff S, Ng PC (2009) Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protoc 4(7):1073–1081
Ledley FD (1990) Perspectives on methylmalonic acidemia resulting from molecular cloning of methylmalonyl CoA mutase. Bioessays 12(7):335–340
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):219–225
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 WA
Manoli I, Myles JG, Sloan JL, Shchelochkov OA, Venditti CP (2016) A critical reappraisal of dietary practices in methylmalonic acidemia raises concerns about the safety of medical foods. Part 1: isolated methylmalonic acidemias. Genet Med 18(4):386–395
Matsui SM, Mahoney MJ, Rosenberg LE (1983) The natural history of the inherited methylmalonic acidemias. N Engl J Med 308(15):857–861
Melo DR, Kowaltowski AJ, Wajner M, Castilho RF (2011) Mitochondrial energy metabolism in neurodegeneration associated with methylmalonic acidemia. J Bioenerg Biomembr 43(1):39–46
Miller SA, Dykes DD, Polesky HF (1988) A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 16(3):1215
Narayanan MP, Kannan V, Vinayan KP, Vasudevan DM (2011) Diagnosis of major organic acidurias in children: two years experience at a tertiary care centre. Indian J Clin Biochem 26(4):347–353
Ogasawara M, Matsubara Y, Mikami H, Narisawa K (1994) Identification of two novel mutations in the methylmalonyl-CoA mutase gene with decreased levels of mutant mRNA in methylmalonic acidemia. Hum Mol Genet 3(6):867–872
O'Shea CJ, Sloan JL, Wiggs EA, Pao M, Gropman A, Baker EH, Manoli I, Venditti CP, Snow J (2012) Neurocognitive phenotype of isolated methylmalonic acidemia. Pediatrics 129(6):e1541–e1551
Richards S et al (2015) Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 17(5):405–424
Saadat M, Ansari-Lari M, Farhud DD (2004) Consanguineous marriage in Iran. Ann Hum Biol 31(2):263–269
Schwarz JM, Cooper DN, Schuelke M, Seelow D (2014) MutationTaster2: mutation prediction for the deep-sequencing age. Nat Methods 11(4):361–362
Tanpaiboon P (2005) Methylmalonic acidemia (MMA). Mol Genet Metab 85(1):2–6
Wajner M, Goodman SI (2011) Disruption of mitochondrial homeostasis in organic acidurias: insights from human and animal studies. J Bioenerg Biomembr 43(1):31–38
Wang F, Han L, Ye J, Qiu W, Zhang Y, Gao X, Wang Y, Yang Y, Gu X (2009) Analysis of the MUT gene mutations in patients with methylmalonic acidemia. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 26(5):485–489
Worgan LC, Niles K, Tirone JC, Hofmann A, Verner A, Sammak A, Kucic T, Lepage P, Rosenblatt DS (2006) Spectrum of mutations in mut methylmalonic acidemia and identification of a common Hispanic mutation and haplotype. Hum Mutat 27(1):31–43
Wynn RM, Davie JR, Chuang JL, Cote CD, Chuang DT (1998) Impaired assembly of E1 decarboxylase of the branched-chain alpha-ketoacid dehydrogenase complex in type IA maple syrup urine disease. J Biol Chem 273(21):13110–13118
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Shafaat, M., Alaee, M.R., Rahmanifar, A. et al. Autozygosity mapping of methylmalonic acidemia associated genes by short tandem repeat markers facilitates the identification of five novel mutations in an Iranian patient cohort. Metab Brain Dis 33, 1689–1697 (2018). https://doi.org/10.1007/s11011-018-0277-4
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DOI: https://doi.org/10.1007/s11011-018-0277-4