Mutation analysis of genes related to methylmalonic acidemia: identification of eight novel mutations

  • Fatemeh Keyfi
  • Mohammad R. Abbaszadegan
  • Mojtaba Sankian
  • Arndt Rolfs
  • Slobodanka Orolicki
  • Mohammad Pournasrollah
  • Morteza Alijanpour
  • Abdolreza VarastehEmail author
Original Article


Methylmalonic acidemia (MMA), an inherited metabolic disease, results from genetic defects in methylmalonyl-CoA mutase or any of the proteins involved in adenosylcobalamin synthesis. This enzyme is classified into several complementation groups and genotypic classes. In this work we explain the biochemical, structural and genetic analysis of 25 MMA patients, from Iran. The diagnosis was established by the measurement of propionylcarnitine in blood using tandem mass spectrometry and confirmed using a gas chromatography–flame ionization detector. Using clinical, biochemical, structural and molecular analyses we identified 15 mut MMA, three cblA, one cblB, and four cblC-deficient patients. Among mutations identified in the MUT gene (MUT) only one, the c.1874A>C (p.D625A) variant, is likely a mut mutation. The remaining mutations are probably mut0. Here, we present the first molecular analysis of MMA in Iranian patients and have identified eight novel mutations. Four novel mutations (p.D625A, p.R326G, p.V157F, p.F379L) were seen exclusively in patients from northern Iran. One novel splice site mutation (c.2125-3C>G) in MUT and two novel mutation (p.N225M and p.A99P) in the MMAA gene were associated with patients from eastern Iran. The rs184829210 SNP was recognized only in patients with the novel c.958G>A (p.A320T) mutation. This study confirms pathogenesis of deficient enzyme activity in MUT, MMAA, MMAB, and MMACHC as previous observations. These results could act as a basis for the performance of pharmacological therapies for increasing the activity of proteins derived from these mutations.


Mutation analysis MUT MMAA MMAB MMACHC Biochemical analysis Novel mutation Methylmalonic acidemia Iranian population 







Complementary DNA


Gas chromatography–flame ionization detector


Human gene mutation database


Methylmalonyl-CoA mutase




Methylmalonic acidemia


Maple syrup urine disease


Mashhad University of Medical Sciences


Propionic acidemia


Reverse transcriptase-polymerase chain reaction


Single nucleotide polymorphism



This research was supported and funded by the Immunology Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.

Compliance with ethical standards

Conflict of interest

All authors declare they have no conflicts of interest.

Supplementary material

11033_2018_4469_MOESM1_ESM.jpg (254 kb)
Supplementary Figure 1 Three-dimensional structures of normal and mutant MUT proteins with novel mutation (D625A). Whole view of the mutant protein (Left Above), close-up view of the mutant protein (Left Below), whole view of the normal protein (Right Above), and close-up view of the normal protein (Right Below). (JPG 254 KB)
11033_2018_4469_MOESM2_ESM.jpg (250 kb)
Supplementary Figure 2 Three-dimensional structures of normal and mutant MUT proteins with novel mutation (R326G). Whole view of the mutant protein (Left Above), close-up view of the mutant protein (Left Below), whole view of the normal protein (Right Above), and close-up view of the normal protein (Right Below). (JPG 250 KB)
11033_2018_4469_MOESM3_ESM.jpg (231 kb)
Supplementary Figure 3 Three-dimensional structures of normal and mutant MUT proteins with novel mutation (V157F). Whole view of the mutant protein (Left Above), close-up view of the mutant protein (Left Below), whole view of the normal protein (Right Above), and close-up view of the normal protein (Right Below). (JPG 230 KB)
11033_2018_4469_MOESM4_ESM.jpg (253 kb)
Supplementary Figure 4 Three-dimensional structures of normal and mutant MUT proteins representing novel mutation (A320T), whole view of the mutant protein (Left Above), close-up view of the mutant protein (Left Below), whole view of the normal protein (Right Above), and close-up view of the normal protein (Right Below). (JPG 252 KB)


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Copyright information

© Springer Nature B.V. 2019

Authors and Affiliations

  • Fatemeh Keyfi
    • 1
    • 2
    • 5
  • Mohammad R. Abbaszadegan
    • 4
  • Mojtaba Sankian
    • 5
  • Arndt Rolfs
    • 6
    • 7
  • Slobodanka Orolicki
    • 8
  • Mohammad Pournasrollah
    • 9
  • Morteza Alijanpour
    • 9
  • Abdolreza Varasteh
    • 1
    • 2
    • 3
    Email author
  1. 1.Department of Medical Laboratory SciencesVarastegan Institute for Medical SciencesMashhadIran
  2. 2.Division of Metabolic disordersPardis Clinical and Genetic LaboratoryMashhadIran
  3. 3.Allergy Research CenterMashhad University of Medical SciencesMashhadIran
  4. 4.Division of Human Genetics, Immunology Research Center, Avicenna Research InstituteMashhad University of Medical SciencesMashhadIran
  5. 5.Immunology Research Center, School of MedicineMashhad University of Medical SciencesMashhadIran
  6. 6.Albrecht Kossel Institute for NeuroregenerationUniversity of RostockRostockGermany
  7. 7.Chief Medical Director, Centogene AGRostockGermany
  8. 8.Clinical and medical scientist, Centogene AGRostockGermany
  9. 9.Non-contagious pediatric disease Research CenterBabol University of Medical SciencesBabolIran

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