Four novel mutations identified in Norwegian patients result in intermittent maple syrup urine disease when combined with the R301C mutation.
Mol Genet Metab
; 100(4): 324-32, 2010 Aug.
Article
em En
| MEDLINE
| ID: mdl-20570198
ABSTRACT
Maple syrup urine disease (MSUD) is caused by a defect in branched chain alpha-ketoacid dehydrogenase complex (BCKD), an essential metabolon for the catabolism of the branched chain amino acids. Here, we report four novel mutations in the DBT gene, encoding the transacylase subunit (E2) of BCKD, resulting in intermittent MSUD in seven Norwegian patients. The patients had episodes with neurological symptoms including lethargy and/or ataxia during childhood infections. All seven patients were heterozygous for the annotated R301C mutation. The second allelic mutations were identified in five patients; one nonsense mutation (G62X), two missense mutations (W84C and R376C) and a mutation in the 3' untranslated region (UTR; c. *358A>C) in two patients. These four novel mutations result in near depletion of E2 protein, and the common R301C protein contributes predominantly to the residual (14%) cellular BCKD activity. Structural analyses of the mutations implied that the W84C and R376C mutations affect stability of intramolecular domains in E2, while the R301C mutation likely disturbs E2 trimer assembly as previously reported. The UTR mutated allele coincided with a strong reduction in mRNA levels, as did the non-R301C specific allele in two patients where the second mutation could not be identified. In summary, the pathogenic effect of the novel mutations is depletion of cellular protein, and the intermittent form of MSUD appears to be attributed to the residual R301C mutant protein in these patients.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Aciltransferases
/
Substituição de Aminoácidos
/
Doença da Urina de Xarope de Bordo
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Mutação
Limite:
Child
/
Child, preschool
/
Humans
/
Infant
País/Região como assunto:
Europa
Idioma:
En
Revista:
Mol Genet Metab
Assunto da revista:
BIOLOGIA MOLECULAR
/
BIOQUIMICA
/
METABOLISMO
Ano de publicação:
2010
Tipo de documento:
Article
País de afiliação:
Noruega