Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0025362 (mental retardation)
 15,878 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Maple syrup urine disease (MSUD) or branched-chain alpha-ketoaciduria is an autosomally inherited disorder in the catabolism of branched-chain amino acids leucine, isoleucine, and valine. The disease is characterized by severe ketoacidosis, mental retardation, and neurological impairments. MSUD can be classified into genetic subtypes according to the genes of the branched-chain alpha-ketoacid dehydrogenase (BCKD) complex which are affected in patients. We describe here four intronic deletions and an intronic nucleotide substitution in the E2 transacylase gene of type II MSUD, in which the E2 subunit of the BCKD complex is deficient. These new E2 mutations comprise an internal 3.2-kb deletion in intron 4 (causing a 17-bp insertion in mRNA), an internal 12-bp (ttaccttgttac) deletion in intron 4 (creating a 10-bp insertion), a 10-bp (catttctaG) deletion in intron 10/ exon 11 junction (leading to a 21-bp deletion), a 2-bp deletion in the exon 5/intron 5 junction (ATgt--> A-t) (resulting in the skipping of exon 5), and a G to A transition at nucleotide -7 of intron 9 (causing a 6-bp insertion). These intronic mutations were initially detected by secondary alterations in the mutant E2 mRNA, as a result of aberrant splicing. The 3.2-kb deletion in intron 4 was determined by the amplification of the entire intron from both a normal subject (11.2 kb) and a homozygous patient (8 kb) by long PCR, followed by subcloning and sequencing of regions flanking the deletion. Similar methods were used to identify and characterize the other intronic alterations. Our results depict heretofore undescribed splicing errors caused by the deletion of internal intronic segments, and provide an approach for detecting this class of novel and rare human mutation. The association of the thiamine-responsive phenotype with a subset of the type II MSUD patients studied is also discussed.
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PMID:E2 transacylase-deficient (type II) maple syrup urine disease. Aberrant splicing of E2 mRNA caused by internal intronic deletions and association with thiamine-responsive phenotype. 923 22

Maple syrup urine disease is caused by deficiency in the mitochondrial branched-chain alpha-ketoacid dehydrogenase (BCKD) complex. The clinical phenotype includes often fatal ketoacidosis, neurological derangement, and mental retardation. The type IA mutations Y393N-alpha, Y368C-alpha, and F364C-alpha, which occur in the E1alpha subunit of the decarboxylase (E1) component of the BCKD complex, impede the conversion of an alphabeta heterodimeric intermediate to a native alpha(2)beta(2) heterotetramer in the E1 assembly pathway. In the present study, we show that a natural osmolyte trimethylamine N-oxide (TMAO) at the optimal 1 m concentration restores E1 activity, up to 50% of the wild type, in the mutant E1 carrying the above missense mutations. TMAO promotes the conversion of otherwise trapped mutant heterodimers to active heterotetramers. This slow step does not involve dissociation/reassociation of the mutant heterodimers, which are preformed in the presence of chaperonins GroEL/GroES and Mg-ATP. The TMAO-stimulated mutant E1 activity is remarkably stable upon removal of the osmolyte, when cofactor thiamine pyrophosphate and the transacylase component of the BCKD complex are present. The above in vitro results offer the use of chemical chaperones such as TMAO as an approach to mitigate assembly defects caused by maple syrup urine disease mutations.
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PMID:Natural osmolyte trimethylamine N-oxide corrects assembly defects of mutant branched-chain alpha-ketoacid decarboxylase in maple syrup urine disease. 1150 2

Analysis of zebrafish mutants that demonstrate abnormal locomotive behavior can elucidate the molecular requirements for neural network function and provide new models of human disease. Here, we show that zebrafish quetschkommode (que) mutant larvae exhibit a progressive locomotor defect that culminates in unusual nose-to-tail compressions and an inability to swim. Correspondingly, extracellular peripheral nerve recordings show that que mutants demonstrate abnormal locomotor output to the axial muscles used for swimming. Using positional cloning and candidate gene analysis, we reveal that a point mutation disrupts the gene encoding dihydrolipoamide branched-chain transacylase E2 (Dbt), a component of a mitochondrial enzyme complex, to generate the que phenotype. In humans, mutation of the DBT gene causes maple syrup urine disease (MSUD), a disorder of branched-chain amino acid metabolism that can result in mental retardation, severe dystonia, profound neurological damage and death. que mutants harbor abnormal amino acid levels, similar to MSUD patients and consistent with an error in branched-chain amino acid metabolism. que mutants also contain markedly reduced levels of the neurotransmitter glutamate within the brain and spinal cord, which probably contributes to their abnormal spinal cord locomotor output and aberrant motility behavior, a trait that probably represents severe dystonia in larval zebrafish. Taken together, these data illustrate how defects in branched-chain amino acid metabolism can disrupt nervous system development and/or function, and establish zebrafish que mutants as a model to better understand MSUD.
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PMID:Mutation of zebrafish dihydrolipoamide branched-chain transacylase E2 results in motor dysfunction and models maple syrup urine disease. 2273 Apr 71