Molecular and structural analyses of maple syrup urine disease and identification of a founder mutation in a Portuguese Gypsy community

Sofia Quental, Sandra Macedo-Ribeiro, Raquel Matos, Laura Vilarinho, Esmeralda Martins, Elisa Leão Teles, Esmeralda Rodrigues, Luísa Diogo, Paula Garcia, Filomena Eusébio, Ana Gaspar, Sílvia Sequeira, Fátima Furtado, Isabel Lança, António Amorim, Maria João Prata
Molecular Genetics and Metabolism 2008, 94 (2): 148-56
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.

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