Molecular and structural analyses of maple syrup urine disease and identification of a founder mutation in a Portuguese Gypsy community.
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.
Quental
Sofia
S
IPATIMUP-Institute of Pathology and Molecular Immunology of University of Porto, Rua Dr. Roberto Frias, s/n, 4200-465 Porto, Portugal. mquental@ipatimup.pt
Macedo-Ribeiro
Sandra
S
Matos
Raquel
R
Vilarinho
Laura
L
Martins
Esmeralda
E
Teles
Elisa Leão
EL
Rodrigues
Esmeralda
E
Diogo
Luísa
L
Garcia
Paula
P
Eusébio
Filomena
F
Gaspar
Ana
A
Sequeira
Sílvia
S
Furtado
Fátima
F
Lança
Isabel
I
Amorim
António
A
Prata
Maria João
MJ
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
D000597:Amino Acids, Branched-Chain; D009097:Multienzyme Complexes; D042942:3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)