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Identification of Six Novel Mutations in Iranian Patients With Maple Syrup Urine Disease and Their in Silico Analysis Publisher Pubmed



Abiri M1, 2 ; Karamzadeh R3, 4 ; Karimipoor M2 ; Ghadami S2 ; Alaei MR5 ; Bagheri SD6 ; Bagherian H6 ; Setoodeh A7 ; Nooridaloii MR1 ; Zeinali S2, 6
Authors
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Authors Affiliations
  1. 1. Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
  2. 2. Department of Molecular Medicine, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran
  3. 3. Department of Molecular Systems Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
  4. 4. Department of Biophysics, Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran
  5. 5. Pediatric Endocrinology and Metabolism, Mofid Children's Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
  6. 6. Dr. Zeinali's Medical Genetics Laboratory, Kawsar Human Genetics Research Center, Vali Asr St., Tehran, 1595645513, Iran
  7. 7. Department of Pediatrics, Tehran University of Medical Sciences, Tehran, Iran

Source: Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis Published:2016


Abstract

Maple syrup urine disease (MSUD) is a rare inborn error of branched-chain amino acid metabolism. The disease prevalence is higher in populations with elevated rate of consanguineous marriages such as Iran. Different types of disease causing mutations have been previously reported in BCKDHA, BCKDHB, DBT and DLD genes known to be responsible for MSUD phenotype.In this study, two sets of multiplex polymorphic STR (Short Tandem Repeat) markers linked to the above genes were used to aid in homozygosity mapping in order to find probable pathogenic change(s) in the studied families. The families who showed homozygote haplotype for the BCKDHA gene were subsequently sequenced. Our findings showed that exons 2, 4 and 6 contain most of the mutations which are novel. The changes include two single nucleotide deletion (i.e. c. 143delT and c.702delT), one gross deletion covering the whole exon four c.(375 + 1_376-1)_(884 9+ 1_885-1), two splice site changes (c.1167 + 1G > T, c. 288 + 1G > A), and one point mutation (c.731G > A). Computational approaches were used to analyze these two novel mutations in terms of their impact on protein structure. Computational structural modeling indicated that these mutations might affect structural stability and multimeric assembly of branched-chain α-keto acid dehydrogenase complex (BCKDC). © 2016.
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