title: In silico analysis of novel mutations in maple syrup urine disease patients from Iran.
abstract: Maple Syrup Urine Disease (MSUD) is a rare autosomal recessive disorder of branched-chain amino acid (BCAA) metabolism. The disease is mainly caused by mutations either in the BCKDHA, BCKDHB, DBT or DLD genes encoding components of the E1α, E1β, E2 and E3 subunits of branched-chain α-keto acid dehydrogenase complex (BCKDC), respectively. BCKDC is a mitochondrial enzyme which is responsible for the normal breakdown of BCAA. The rate of consanguineous marriage in Iran is 38.6 %, so the prevalence of autosomal recessive disorders is higher in comparison to other countries. Consanguinity increases the chance of the presence of pathogenic mutations in a homoallelic state. This phenomenon has made homozygosity mapping a powerful tool for finding the probable causative gene in heterogeneous disorders like IEM (Inborn Errors of Metabolism). In this study, two sets of multiplex polymorphic STR (Short Tandem Repeat) markers linked to the above-mentioned genes were selected to identify the probable pathogenic gene in the studied families. The families who showed a homozygous haplotype for the STR markers of the BCKDHB gene were subsequently sequenced. Four novel mutations including c.633 + 1G > A, c.988G > A, c.833_834insCAC, and a homozygous deletion of whole exon 3 c. (274 + 1_275-1) _(343 + 1_344-1), as well as one recently reported (c. 508G > T) mutation have been identified. Interestingly, three families shared a common haplotype structure along with the c. 508G > T mutation. Also, four other families revealed another similar haplotype with c.988G > A mutation. Founder effect can be a suggestive mechanism for the disease. Additionally, structural models of MSUD mutations have been performed to predict the pathogenesis of the newly identified variants.
authors: Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Pasteur St, Tehran, Iran.|Department of Molecular Medicine, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran.
authors: Maryam
authors: M
authors: Abiri
authors: Department of Molecular Systems Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.|Department of Biophysics, Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran.
authors: Razieh
authors: R
authors: Karamzadeh
authors: Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Pasteur St, Tehran, Iran.|Department of Molecular Medicine, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran.
authors: Marziyeh
authors: M
authors: Mojbafan
authors: Pediatric Endocrinology and Metabolism, Mofid Children's Hospital, Tehran, Iran.|Pediatric Endocrinology and Metabolism, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
authors: Mohammad Reza
authors: MR
authors: Alaei
authors: Dr. Zeinali's Medical Genetics Laboratory, Kawsar Human Genetics Research Center, No. 41 Majlesi St., Vali Asr St, Tehran, 1595645513, Iran.
authors: Atefeh
authors: A
authors: Jodaki
authors: Path biology lab, Pars hospital, Tehran, Iran.
authors: Masomeh
authors: M
authors: Safi
authors: Dr. Zeinali's Medical Genetics Laboratory, Kawsar Human Genetics Research Center, No. 41 Majlesi St., Vali Asr St, Tehran, 1595645513, Iran.
authors: Soodeh
authors: S
authors: Kianfar
authors: Dr. Zeinali's Medical Genetics Laboratory, Kawsar Human Genetics Research Center, No. 41 Majlesi St., Vali Asr St, Tehran, 1595645513, Iran.|Science and Research Branch, Islamic Azad University, Tehran, Iran.
authors: Ameneh
authors: A
authors: Bandehi Sarhaddi
authors: Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Pasteur St, Tehran, Iran.
authors: Mohammad Reza
authors: MR
authors: Noori-Daloii
authors: Department of Molecular Medicine, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran.
authors: Morteza
authors: M
authors: Karimipoor
authors: Department of Molecular Medicine, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran. zeinali@kawsar.ir.|Dr. Zeinali's Medical Genetics Laboratory, Kawsar Human Genetics Research Center, No. 41 Majlesi St., Vali Asr St, Tehran, 1595645513, Iran. zeinali@kawsar.ir.
authors: Sirous
authors: S
authors: Zeinali
mesh_terms: D000597:Amino Acids, Branched-Chain / Q000235:genetics*; D003198:Computer Simulation; D004252:DNA Mutational Analysis; D005260:Female; D006239:Haplotypes; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007492:Iran; D008297:Male; D008375:Maple Syrup Urine Disease / Q000235:genetics*; D018895:Microsatellite Repeats; D009154:Mutation
chemical_list: D000597:Amino Acids, Branched-Chain
keywords: BCKDHB gene; Iran; MSUD; Mutation analysis