title: Molecular and structural analyses of maple syrup urine disease and identification of a founder mutation in a Portuguese Gypsy community.
abstract: Maple syrup urine disease (MSUD) is an autosomal recessive disorder, caused by the defective function of the branched-chain alpha-ketoacid dehydrogenase complex (BCKD). BCKD is a mitochondrial complex, encoded by four nuclear genes (BCKDHA, BCKDHB, DBT and DLD), involved in the metabolism of branched-chain amino acids (BCAAs). Since the MSUD mutational spectrum has not been previously assessed in Portugal, in this study we present the molecular characterization of 30 MSUD Portuguese patients. Seventeen putative mutations have been identified (six in BCKDHA, five in BCKDHB and six in DBT); seven of them are here described for the first time. The most common mutation identified was a C deletion in BCKDHA gene (c.117delC; p.R40GfsX23), already reported in the Spanish population. Interestingly, it was found in all patients of a Gypsy community from South of the country, so a founder effect is probably responsible for the high incidence of the disease in this community. Structural models of MSUD missense mutations have been performed to understand their pathogenic effect, in order to elucidate and often to predict the severity of a mutation clinical consequence.
authors: IPATIMUP-Institute of Pathology and Molecular Immunology of University of Porto, Rua Dr. Roberto Frias, s/n, 4200-465 Porto, Portugal. mquental@ipatimup.pt
authors: Sofia
authors: S
authors: Quental
authors: Sandra
authors: S
authors: Macedo-Ribeiro
authors: Raquel
authors: R
authors: Matos
authors: Laura
authors: L
authors: Vilarinho
authors: Esmeralda
authors: E
authors: Martins
authors: Elisa Leão
authors: EL
authors: Teles
authors: Esmeralda
authors: E
authors: Rodrigues
authors: Luísa
authors: L
authors: Diogo
authors: Paula
authors: P
authors: Garcia
authors: Filomena
authors: F
authors: Eusébio
authors: Ana
authors: A
authors: Gaspar
authors: Sílvia
authors: S
authors: Sequeira
authors: Fátima
authors: F
authors: Furtado
authors: Isabel
authors: I
authors: Lança
authors: António
authors: A
authors: Amorim
authors: Maria João
authors: MJ
authors: Prata
mesh_terms: D042942:3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide) / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D000597:Amino Acids, Branched-Chain / Q000097:blood; D005260:Female; D006801:Humans; D008297:Male; D008375:Maple Syrup Urine Disease / Q000235:genetics*; D008969:Molecular Sequence Data; D009097:Multienzyme Complexes / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D020125:Mutation, Missense; D011174:Portugal; D006178:Romani People / Q000235:genetics*; D053719:Tandem Mass Spectrometry
chemical_list: D000597:Amino Acids, Branched-Chain; D009097:Multienzyme Complexes; D042942:3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)