Two new mutations in the human E1β subunit of branched chain α-ketoacid dehydrogenase associated with maple syrup urine disease

McConnell, Beth B.; Burkholder, Brett; Danner, Dean J.

doi:10.1016/s0925-4439(97)00046-x

Cited by 18 publications

(10 citation statements)

References 24 publications

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“…Since all cells with mitochondria express BCKD, any cell of this type can be used; most often transformed lymphocytes. Analysis of DNA from the parents confirms inheritance and identifies the parental origin of each mutant allele (75,78). Only one mutation is found with an increased frequency, the 1325T→A transversion that results in a Y393N substitution in E1α.…”

Section: Molecular Genetics Of Bckdmentioning

confidence: 80%

“…The number of mutations identified in E1β are far less than those known for E1α. Functional analysis of two E1β mutations have been reported (78). One mutation results in a substitution of tyrosine for asparagine126 and the second truncates the protein at arginine274, shortening the subunit by 68 amino acids.…”

Section: Lessons Learned From Functional Analysis Of Msud Mutationsmentioning

confidence: 99%

“…The other mutant allele product with a single amino acid substitution does interact with E1α to form the BCKD complex, yet catalytic activity is absent (78). Based on computer alignment of the α 2 β 2 structure with the crystal structure of transketolase, it has be speculated that this amino acid substitution interferes with TPP binding.…”

Section: Lessons Learned From Functional Analysis Of Msud Mutationsmentioning

confidence: 99%

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Human mutations affecting branched chain a-ketoacid dehydrogenase

Danner

Doering²

1998

Front Biosci

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Section: Molecular Genetics Of Bckdmentioning

confidence: 80%

Section: Lessons Learned From Functional Analysis Of Msud Mutationsmentioning

confidence: 99%

Section: Lessons Learned From Functional Analysis Of Msud Mutationsmentioning

confidence: 99%

See 1 more Smart Citation

Human mutations affecting branched chain a-ketoacid dehydrogenase

Danner

Doering²

1998

Front Biosci

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“…Heterozygotes express 50% of BCKDH activity (12). Usually, this is enough to prevent any phenotypical expression (13). …”

Section: Discussionmentioning

confidence: 99%

Successful domino liver transplantation in maple syrup urine disease using a related living donor

Feier

Miura

Fonseca

et al. 2014

Braz J Med Biol Res

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Maple syrup urine disease (MSUD) is an autosomal recessive disease associated with high levels of branched-chain amino acids. Children with MSUD can present severe neurological damage, but liver transplantation (LT) allows the patient to resume a normal diet and avoid further neurological damage. The use of living related donors has been controversial because parents are obligatory heterozygotes. We report a case of a 2-year-old child with MSUD who underwent a living donor LT. The donor was the patient's mother, and his liver was then used as a domino graft. The postoperative course was uneventful in all three subjects. DNA analysis performed after the transplantation (sequencing of the coding regions of BCKDHA, BCKDHB, and DBT genes) showed that the MSUD patient was heterozygous for a pathogenic mutation in the BCKDHB gene. This mutation was not found in his mother, who is an obligatory carrier for MSUD according to the family history and, as expected, presented both normal clinical phenotype and levels of branched-chain amino acids. In conclusion, our data suggest that the use of a related donor in LT for MSUD was effective, and the liver of the MSUD patient was successfully used in domino transplantation. Routine donor genotyping may not be feasible, because the test is not widely available, and, most importantly, the disease is associated with both the presence of allelic and locus heterogeneity. Further studies with this population of patients are required to expand the use of related donors in MSUD.

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“…Cells were placed in serum-free F-12K media for 20 h and then treated with insulin as above for 20 h (6 wells/treatment). The BCKD kinase inhibitor ␣-chloroisocaproate (CIC; 1 mM) was added to three of the six wells for each experimental condition, and the plates were incubated at 37°C for 10 min before initiation of the BCKD assay by addition of [1-14 C]leucine (0.5 Ci/reaction) made to 430 M with unlabeled leucine (33). Incubation with CIC allows endogenous activation of BCKD for assessment of total BCKD activity within the cells.…”

Section: Methodsmentioning

confidence: 99%

Insulin increases branched-chain α-ketoacid dehydrogenase kinase expression in Clone 9 rat cells

Nellis

Doering²,

Kasinski³

et al. 2002

American Journal of Physiology-Endocrinology and Metabolism

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Nellis, Mary M., Christopher B. Doering, Andrea Kasinski, and Dean J. Danner. Insulin increases branchedchain ␣-ketoacid dehydrogenase kinase expression in Clone 9 rat cells. Am J Physiol Endocrinol Metab 283: E853-E860, 2002. First published June 3, 2002 10.1152/ajpendo.00133.2002The branched-chain amino acids (BCAA) are committed to catabolism by the activity of the branched-chain ␣-ketoacid dehydrogenase (BCKD) complex. BCKD activity is regulated through the action of the complex-specific BCKD kinase that phosphorylates two serine residues in the E1␣ subunit. Greater BCKD kinase expression levels result in a lower activity state of BCKD and thus a decreased rate of BCAA catabolism. Activity state varies among tissues and can be altered by diet, exercise, hormones, and disease state. Within individual tissues, the concentration of BCKD kinase reflects the activity state of the BCKD complex. Here we investigated the effects of insulin, an important regulator of hepatic metabolic enzymes, on BCKD kinase expression in Clone 9 rat cells. Insulin effected a twofold increase in message levels and a twofold increase in BCKD kinase protein levels. The response was completely blocked by treatment with LY-294002 and partially blocked by rapamycin, thus demonstrating a dependence on phosphatidylinositol 3-kinase and mTOR function, respectively. These studies suggest that insulin acts to regulate BCAA catabolism through stimulation of BCKD kinase expression.hormone-controlled gene expression; branched-chain amino acids THE BRANCHED-CHAIN amino acids (BCAA), leucine, isoleucine, and valine, are classified as essential components of the mammalian diet because they cannot be synthesized de novo. BCAA account for up to 20% of the residues in the average protein. Catabolism of the BCAA provides energy, and their products serve as precursors for fatty acid synthesis. BCAA can modify other metabolic processes through a poorly understood mechanism whereby cells sense the concentration of these amino acids. Protein turnover, especially in the liver and muscles, is slowed when the BCAA concentration is maintained (6,12,32,37,38).Another player in the cellular regulation of protein turnover is insulin, which stimulates protein synthesis, especially in liver (11,15). A combination of insulin and leucine may be needed for the promotion of protein synthesis, and this action may occur through separate pathways to enhance assembly of the translation initiation complex (2, 5, 22). As expected, because tissues respond differently to insulin exposure, tissue-specific variation in these effects is reported (9,19,35,40).Maintenance of cellular BCAA concentration in mammals results from a balance between supply and catabolic loss. Supply results from dietary intake or breakdown of endogenous protein. Irreversible loss results from catabolism of the BCAA that begins with their reversible transamination to yield the branchedchain ␣-ketoacids (BCKA). Oxidative decarboxylation of the BCKA commits these compounds to their catabolic fate. The react...

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Two new mutations in the human E1β subunit of branched chain α-ketoacid dehydrogenase associated with maple syrup urine disease

Cited by 18 publications

References 24 publications

Human mutations affecting branched chain a-ketoacid dehydrogenase

Human mutations affecting branched chain a-ketoacid dehydrogenase

Successful domino liver transplantation in maple syrup urine disease using a related living donor

Insulin increases branched-chain α-ketoacid dehydrogenase kinase expression in Clone 9 rat cells

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