Volume 27, Issue 6 (11-2023)                   IBJ 2023, 27(6): 397-403 | Back to browse issues page

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Jafari M, Karami F, Setoodeh A, Rahmanifar A, Bagherian H, Alaei M R, et al . Identification of Novel Mutations in the MMAA and MUT Genes among Methylmalonic Aciduria Families. IBJ 2023; 27 (6) :397-403
URL: http://ibj.pasteur.ac.ir/article-1-3782-en.html
Background: Methylmalonic aciduria (MMA) is a rare inherited metabolic disorder with autosomal recessive inheritance pattern. There are still MMA patients without known mutations in the responsible genes. This study aimed to identify mutations in Iranian MMA families using autozygosity mapping and next generation sequencing (NGS).
Methods: Multiplex PCR was performed on DNAs isolated from 12 unrelated MMA patients and their family members using 19 STR markers flanking MUT, MMAA, and MMAB genes, followed by Sanger sequencing. Whole exome sequencing was carried out in the patients with no mutation.
Results: Haplotype analysis and Sanger sequencing revealed two novel, mutations, A252Vf*5 and G87R, within the MMAA and MUT genes, respectively. Three patients showed no mutations in either autozygosity mapping or NGS analysis.
Conclusion: High-frequency mutations within exons 2 and 3 of MUT gene and exon 7 of MMAB gene are consistent with the global expected frequency of genetic variations among MMA patients.

1. Jin L, Han X, He F, Zhang C. Prevalence of methylmalonic acidemia among newborns and the clinical-suspected population: a meta-analyse. The journal of maternal-fetal and neonatal medicine 2022; 35(25): 8952-8967. [DOI:10.1080/14767058.2021.2008351]
2. Elliott AM. Genetic counseling and genome sequencing in pediatric rare disease. Cold spring harbor perspectives in medicine 2020; 10(3) :a036632. [DOI:10.1101/cshperspect.a036632]
3. Tiivoja E, Reinson K, Muru K, Rähn K, Muhu K, Mauring L, Kahre T, Pajusalu P, Õunap K. The prevalence of inherited metabolic disorders in Estonian population over 30 years: a significant increase during study period. JIMD reports 2022; 63(6): 604-613. [DOI:10.1002/jmd2.12325]
4. Manoli I, Myles JG, Sloan JL, Shchelochkov OA, Venditti CP. A critical reappraisal of dietary practices in methylmalonic acidemia raises concerns about the safety of medical foods. Part 1: isolated methylmalonic acidemias. Genetics in medicine : official journal of the american college of medical genetics 2016; 18(4): 386-395. [DOI:10.1038/gim.2015.102]
5. Forny P, Hörster F, Ballhausen D, Chakrapani A, Chapman KA, Dionisi-Vici C, Dixon M, Grünert SC, Grunewald S, Haliloglu G, Hochuli M, Honzik T, Karall D, Martinelli D, Molema F, Sass JO, Scholl-Bürgi S, Tal G, Williams M, Huemer M, Baumgartner MR. Guidelines for the diagnosis and management of methylmalonic acidaemia and propionic acidaemia: First revision. Journal of inherited metabolic disease 2021; 44(3): 566-592. [DOI:10.1002/jimd.12370]
6. Shafaat M, Alaee MR, Rahmanifar A, Setoodeh A, Razzaghy-Azar M, Bagherian H, Dabbagh Bagheri S, Zafarghandi Motlagh F, Hashemi M, Abiri M, Zeinali S. Autozygosity mapping of methylmalonic acidemia associated genes by short tandem repeat markers facilitates the identification of five novel mutations in an Iranian patient cohort. Metabolic brain disease 2018; 33(5): 1689-1697. [DOI:10.1007/s11011-018-0277-4]
7. Keyfi F, Abbaszadegan MR, Rolfs A, Orolicki S, Moghaddassian M, Varasteh A. Identification of a novel deletion in the MMAA gene in two Iranian siblings with vitamin B12-responsive methylmalonic acidemia. Cellular and molecular biology letters 2016; 21: 4. [DOI:10.1186/s11658-016-0005-1]
8. Keyfi F, Sankian M, Moghaddassian M, Rolfs A, Varasteh AR. Molecular, biochemical, and structural analysis of a novel mutation in patients with methylmalonyl-CoA mutase deficiency. Gene 2016; 576(1 Pt 2): 208-213. [DOI:10.1016/j.gene.2015.10.002]
9. Ahmadloo S, Talebi S, Miryounesi M, Pasalar P, Keramatipour M. Functional analysis of a novel splicing mutation in the mutase gene of two unrelated pedigrees. Cell journal 2016; 18(3): 397-404.
10. Campanello GC, Lofgren M, Yokom AL, Southworth DR, Banerjee R. Switch I-dependent allosteric signaling in a G-protein chaperone-B(12) enzyme complex. The journal of biological chemistry 2017; 292(43): 17617-1725. [DOI:10.1074/jbc.M117.786095]
11. Lerner-Ellis JP, Gradinger AB, Watkins D, Tirone JC, Villeneuve A, Dobson CM, Montpetit A, Lepage P, RA, Rosenblatt DS. Mutation and biochemical analysis of patients belonging to the cblB complementation class of vitamin B12-dependent methylmalonic aciduria. Molecular genetics and metabolism 2006; 87(3): 219-225. [DOI:10.1016/j.ymgme.2005.11.011]
12. Zhang J, Wu X, Padovani D, Schubert HL, Gravel RA. Ligand-binding by catalytically inactive mutants of the cblB complementation group defective in human ATP:cob(I)alamin adenosyltransferase. Molecular genetics and metabolism 2009; 98(3): 278-284. [DOI:10.1016/j.ymgme.2009.06.014]
13. Illson M. Spectrum of Mutations in MMAB Identified by High Resolution Melting 2012. Available at: file:///C:/Users/ASUS/Downloads/37c5862e-6782-44dd-8973-3f7394ead93a.pdf.
14. Al-Shamsi A, Hertecant JL, Al-Hamad S, Souid AK, Al-Jasmi F. Mutation spectrum and birth prevalence of inborn errors of metabolism among emiratis: a study from tawam hospital metabolic center, United Arab Emirates. Sultan qaboos university medical journal 2014; 14(1): e42-49. [DOI:10.12816/0003335]
15. Dobson CM, Wai T, Leclerc D, Kadir H, Narang M, Lerner-Ellis JP, Hudson TJ, Rosenblatt DS, Gravel RA. Identification of the gene responsible for the cblB complementation group of vitamin B12-dependent methylmalonic aciduria. Human molecular genetics 2002; 11(26): 3361-3369. [DOI:10.1093/hmg/11.26.3361]
16. Lempp TJ, Suormala T, Siegenthaler R, Baumgartner ER, Fowler B, Steinmann B, Baumgartner MR. Mutation and biochemical analysis of 19 probands with mut0 and 13 with mut- methylmalonic aciduria: identification of seven novel mutations. Molecular genetics and metabolism 2007; 90(3): 284-290. [DOI:10.1016/j.ymgme.2006.10.002]
17. Worgan LC, Niles K, Tirone JC, Hofmann A, Verner A, Sammak A, Kucic T, Lepage P, Rosenblatt DS. Spectrum of mutations in mut methylmalonic acidemia and identification of a common Hispanic mutation and haplotype. Human mutation 2006; 27(1): 31-43. [DOI:10.1002/humu.20258]
18. Lee H, Deignan JL, Dorrani N, Strom SP, Kantarci S, Quintero-Rivera F, Das K, Toy T, Harry B, Yourshaw M, Fox M, Fogel BL, Martinez-Agosto JA, Wong DA, Chang VY, Shieh PB, Palmer CGS, Dipple KM, Grody WW, Vilain E, Nelson SF. Clinical exome sequencing for genetic identification of rare Mendelian disorders. The journal of the american medical association 2014; 312(18): 1880-1887. [DOI:10.1001/jama.2014.14604]
19. Liu MY, Liu TT, Yang YL, Chang YC, Fan YL, Lee SF, Teng YT, Chiang SH, Niu DM, Lin SJ, Chao MC, Lin SP, Han LS, Qi Y, Hsiao KJ. Mutation profile of the MUT gene in chinese methylmalonic aciduria patients. JIMD reports 2012; 6: 55-64. [DOI:10.1007/8904_2011_117]
20. Merinero B, Pérez B, Pérez-Cerdá C, Rincón A, Desviat LR, Martínez MA, Sala PR, García MJ, Aldamiz-Echevarría L, Campos J, Cornejo V, Toro MD, Mahfoud A, Martínez-Pardo M, Parini R, Pedrón C, Peña-Quintana L, Pérez M, Pourfarzam M, Ugarte M. Methylmalonic acidaemia: examination of genotype and biochemical data in 32 patients belonging to mut, cblA or cblB complementation group. Journal of inherited metabolic disease 2008; 31(1): 55-66. [DOI:10.1007/s10545-007-0667-y]
21. Habibzadeh P, Tabatabaei Z, Farazi Fard MA, Jamali L, Hafizi A, Nikuei P, Salarian L, Nasr Esfahani MH, Anvar Z, Faghihi MA. Pre-implantation genetic diagnosis in an Iranian family with a novel mutation in MUT gene. BMC medical genetics 2020; 21(1): 22. [DOI:10.1186/s12881-020-0959-8]
22. Huemer M, Scholl-Bürgi S, Hadaya K, Kern I, Beer R, Seppi K, Fowler B, Baumgartner MR , Karall D . Three new cases of late-onset cblC defect and review of the literature illustrating when to consider inborn errors of metabolism beyond infancy. Orphanet journal of rare diseases 2014; 9: 161. [DOI:10.1186/s13023-014-0161-1]
23. Brasil S, Briso-Montiano A, Gámez A, Underhaug J, Flydal MI, Desviat L, Merinero B, Ugarte M, Martinez A, Pérez B. New perspectives for pharmacological chaperoning treatment in methylmalonic aciduria cblB type. Biochimica et biophysica acta molecular basis of disease 2018; 1864(2): 640-648. [DOI:10.1016/j.bbadis.2017.11.024]
24. Keyfi F, Talebi S, Varasteh AR. Methylmalonic acidemia diagnosis by laboratory methods. Reports of biochemistry & molecular biology 2016; 5(1): 1-14.
25. Jorge-Finnigan A, Aguado C, Sánchez-Alcudia R, Abia D, Richard E, Merinero B, Gámez A, Banerjee R, Desviat LR, Ugarte M, Pérez B. Functional and structural analysis of five mutations identified in methylmalonic aciduria cblB type. Human mutation 2010; 31(9): 1033-1042. [DOI:10.1002/humu.21307]
26. Wang F, Han L, Ye J, Qiu W, Zhang Y, Gao X, Wang Y, Yang Y, Gu X. Analysis of the MUT gene mutations in patients with methylmalonic acidemia. Zhonghua yixue yichuanxue zazhi 2009; 26(5): 485-489.

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