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Autozygosity Mapping of Methylmalonic Acidemia Associated Genes by Short Tandem Repeat Markers Facilitates the Identification of Five Novel Mutations in an Iranian Patient Cohort Publisher Pubmed



Shafaat M1 ; Alaee MR2 ; Rahmanifar A3 ; Setoodeh A4 ; Razzaghyazar M5, 6 ; Bagherian H7 ; Bagheri SD7 ; Zafarghandi Motlagh F7 ; Hashemi M1 ; Abiri M7, 8 ; Zeinali S7, 9
Authors
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Authors Affiliations
  1. 1. Department of Genetics, Islamic Azad University, Tehran Medical Sciences Branch, Tehran, Iran
  2. 2. Pediatric Endocrinology and Metabolism, Mofid Children’s Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
  3. 3. Iranian National Society for Study of Inborn Metabolic Diseases, Tehran, Iran
  4. 4. Department of Pediatrics, Tehran University of Medical Sciences, Tehran, Iran
  5. 5. Metabolic Disorders Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
  6. 6. Hazrat Aliasghar Childrens Hospital, Iran University of Medical Sciences, Tehran, Iran
  7. 7. Medical Genetics Laboratory, Kawsar Human Genetics Research Center, No. 41 Majlesi St., Vali Asr St., Tehran, 1595645513, Iran
  8. 8. Department of Medical Genetics and Molecular Biology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
  9. 9. Department of Molecular Medicine, Biotechnology Research Center, Pasteur Institute of Iran, Pasteur St., Tehran, Iran

Source: Metabolic Brain Disease Published:2018


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