Advertisement

Metabolic Brain Disease

, Volume 33, Issue 5, pp 1689–1697 | Cite as

Autozygosity mapping of methylmalonic acidemia associated genes by short tandem repeat markers facilitates the identification of five novel mutations in an Iranian patient cohort

  • Mehdi Shafaat
  • Mohammad Reza Alaee
  • Ali Rahmanifar
  • Aria Setoodeh
  • Maryam Razzaghy-Azar
  • Hamideh Bagherian
  • Samira Dabbagh Bagheri
  • Fatemeh Zafarghandi Motlagh
  • Mehrdad Hashemi
  • Maryam Abiri
  • Sirous Zeinali
Original Article
  • 21 Downloads

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.

Keywords

Methylmalonic acidemia (MMA) Autozygosity mapping Mutation analysis Iran 

Notes

Compliance with ethical standards

Conflict of interest

There is no conflict of interest to declare.

Informed consent

Informed consent was received from 11 patients for participation in this study.

Animal rights

This study does not contain any animal study.

Supplementary material

11011_2018_277_MOESM1_ESM.pdf (496 kb)
ESM 1 (PDF 495 kb)

References

  1. 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):167–176CrossRefGoogle Scholar
  2. 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):248–249CrossRefGoogle Scholar
  3. Alkhunaizi AM, Al-Sannaa N (2017) Renal involvement in methylmalonic aciduria. Kidney Int Rep 2(5):956–960CrossRefGoogle Scholar
  4. Benson G (1999) Tandem repeats finder: a program to analyze DNA sequences. Nucleic Acids Res 27(2):573–580CrossRefGoogle Scholar
  5. 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):576–581CrossRefGoogle Scholar
  6. 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):363–367CrossRefGoogle Scholar
  7. den Dunnen JT, Antonarakis SE (2000) Mutation nomenclature extensions and suggestions to describe complex mutations: a discussion. Hum Mutat 15(1):7–12CrossRefGoogle Scholar
  8. 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):3361–3369CrossRefGoogle Scholar
  9. 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):745–754CrossRefGoogle Scholar
  10. Hamamy H (2012) Consanguineous marriages : preconception consultation in primary health care settings. J Community Genet 3(3):185–192CrossRefGoogle Scholar
  11. 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):381–386CrossRefGoogle Scholar
  12. 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):345–353CrossRefGoogle Scholar
  13. 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):47–56CrossRefGoogle Scholar
  14. 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):1033–1042CrossRefGoogle Scholar
  15. 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 21:4CrossRefGoogle Scholar
  16. Keyfi F, Talebi S, Varasteh AR (2016b) Methylmalonic acidemia diagnosis by laboratory methods. Rep Biochem Mol Biol 5(1):1–14PubMedPubMedCentralGoogle Scholar
  17. 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):1073–1081CrossRefGoogle Scholar
  18. Ledley FD (1990) Perspectives on methylmalonic acidemia resulting from molecular cloning of methylmalonyl CoA mutase. Bioessays 12(7):335–340CrossRefGoogle Scholar
  19. 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):219–225CrossRefGoogle Scholar
  20. 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
  21. 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):386–395CrossRefGoogle Scholar
  22. Matsui SM, Mahoney MJ, Rosenberg LE (1983) The natural history of the inherited methylmalonic acidemias. N Engl J Med 308(15):857–861CrossRefGoogle Scholar
  23. Melo DR, Kowaltowski AJ, Wajner M, Castilho RF (2011) Mitochondrial energy metabolism in neurodegeneration associated with methylmalonic acidemia. J Bioenerg Biomembr 43(1):39–46CrossRefGoogle Scholar
  24. Miller SA, Dykes DD, Polesky HF (1988) A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 16(3):1215CrossRefGoogle Scholar
  25. 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):347–353CrossRefGoogle Scholar
  26. 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):867–872CrossRefGoogle Scholar
  27. 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–e1551CrossRefGoogle Scholar
  28. 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):405–424CrossRefGoogle Scholar
  29. Saadat M, Ansari-Lari M, Farhud DD (2004) Consanguineous marriage in Iran. Ann Hum Biol 31(2):263–269CrossRefGoogle Scholar
  30. Schwarz JM, Cooper DN, Schuelke M, Seelow D (2014) MutationTaster2: mutation prediction for the deep-sequencing age. Nat Methods 11(4):361–362CrossRefGoogle Scholar
  31. Tanpaiboon P (2005) Methylmalonic acidemia (MMA). Mol Genet Metab 85(1):2–6CrossRefGoogle Scholar
  32. Wajner M, Goodman SI (2011) Disruption of mitochondrial homeostasis in organic acidurias: insights from human and animal studies. J Bioenerg Biomembr 43(1):31–38CrossRefGoogle Scholar
  33. 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):485–489PubMedGoogle Scholar
  34. 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):31–43CrossRefGoogle Scholar
  35. 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):13110–13118CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Mehdi Shafaat
    • 1
  • Mohammad Reza Alaee
    • 2
  • Ali Rahmanifar
    • 3
  • Aria Setoodeh
    • 4
  • Maryam Razzaghy-Azar
    • 5
    • 6
  • Hamideh Bagherian
    • 7
  • Samira Dabbagh Bagheri
    • 7
  • Fatemeh Zafarghandi Motlagh
    • 7
  • Mehrdad Hashemi
    • 1
  • Maryam Abiri
    • 7
    • 8
  • Sirous Zeinali
    • 7
    • 9
  1. 1.Department of GeneticsIslamic Azad University, Tehran Medical Sciences BranchTehranIran
  2. 2.Pediatric Endocrinology and Metabolism, Mofid Children’s HospitalShahid Beheshti University of Medical SciencesTehranIran
  3. 3.Iranian National Society for Study of Inborn Metabolic DiseasesTehranIran
  4. 4.Department of PediatricsTehran University of Medical SciencesTehranIran
  5. 5.Metabolic Disorders Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences InstituteTehran University of Medical SciencesTehranIran
  6. 6.Hazrat Aliasghar Childrens HospitalIran University of Medical SciencesTehranIran
  7. 7.Medical Genetics LaboratoryKawsar Human Genetics Research CenterTehranIran
  8. 8.Department of Medical Genetics and Molecular Biology, School of MedicineIran University of Medical SciencesTehranIran
  9. 9.Department of Molecular Medicine, Biotechnology Research CenterPasteur Institute of IranTehranIran

Personalised recommendations