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

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Abstract

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.

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Abbreviations

AdoCbl:

Adenosylcobalamin

Cbl:

Cobalamin

cDNA:

Complementary DNA

GC–FID:

Gas chromatography–flame ionization detector

HGMD:

Human gene mutation database

MCM:

Methylmalonyl-CoA mutase

MeCbl:

Methylcobalamin

MMA:

Methylmalonic acidemia

MSUD:

Maple syrup urine disease

MUMS:

Mashhad University of Medical Sciences

PA:

Propionic acidemia

RT-PCR:

Reverse transcriptase-polymerase chain reaction

SNP:

Single nucleotide polymorphism

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Acknowledgements

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

Author information

Authors and Affiliations

  1. Department of Medical Laboratory Sciences, Varastegan Institute for Medical Sciences, Mashhad, Iran

    Fatemeh Keyfi & Abdolreza Varasteh

  2. Division of Metabolic disorders, Pardis Clinical and Genetic Laboratory, Mashhad, Iran

    Fatemeh Keyfi & Abdolreza Varasteh

  3. Allergy Research Center, Mashhad University of Medical Sciences, Mashhad, Iran

    Abdolreza Varasteh

  4. Division of Human Genetics, Immunology Research Center, Avicenna Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran

    Mohammad R. Abbaszadegan

  5. Immunology Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

    Fatemeh Keyfi & Mojtaba Sankian

  6. Albrecht Kossel Institute for Neuroregeneration, University of Rostock, Rostock, Germany

    Arndt Rolfs

  7. Chief Medical Director, Centogene AG, Rostock, Germany

    Arndt Rolfs

  8. Clinical and medical scientist, Centogene AG, Rostock, Germany

    Slobodanka Orolicki

  9. Non-contagious pediatric disease Research Center, Babol University of Medical Sciences, Babol, Iran

    Mohammad Pournasrollah & Morteza Alijanpour

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  1. Fatemeh Keyfi
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  2. Mohammad R. Abbaszadegan
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Corresponding author

Correspondence to Abdolreza Varasteh.

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Additional information

Accession Numbers: The accession number for the c.1874A>C, p.D625A reported in this paper is [NCBI]: [KP289323]. The accession number for the c.976A>G/N, p.R326G reported in this paper is [NCBI]: [KP289324]. The accession number for the c.469G>T, p. V157F reported in this paper is [NCBI]: [KR026956]. The accession number for the c.2125-3C>G reported in this paper is [NCBI]: [KF030882]. The accession number for the c.1137del T, p.F379L reported in this paper is [NCBI]: [KR026957]. The accession number for the c.674del A, p.N225M reported in this paper is [NCBI]: [KR026958].

Electronic supplementary material

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11033_2018_4469_MOESM1_ESM.jpg

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

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

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

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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Keyfi, F., Abbaszadegan, M.R., Sankian, M. et al. Mutation analysis of genes related to methylmalonic acidemia: identification of eight novel mutations. Mol Biol Rep 46, 271–285 (2019). https://doi.org/10.1007/s11033-018-4469-0

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