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 AbiriEmail author
  • Sirous ZeinaliEmail author
Original Article


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.


Methylmalonic acidemia (MMA) Autozygosity mapping Mutation analysis Iran 


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)


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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
    Email author
  • Sirous Zeinali
    • 7
    • 9
    Email author
  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

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