DBT loss-of-function mutants don't synthesize BCAA-CoA

Stable Identifier
R-HSA-9865115
Type
Reaction [transition]
Species
Homo sapiens
Compartment
mitochondrial matrix
ReviewStatus
5/5
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DBT loss-of-function mutants don't synthesize BCAA-CoA
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Loss-of-function alleles of DBT are associated with classic, intermittent and thiamine-responsive forms of MSUD (Tsuruta et al, 1998; Fisher et al, 1991; Mitsubishi et al, 1991; Chuang et al, 1997; Ali and Ngu, 2018; reviewed in Strauss et al, 2020; Biswas et al, 2019). Overall, mutations in DBT account for approximately 20% of the presumed pathogenic mutations associated with MSUD, and DBT mutations appear to arise more frequently through deletion events than is observed for MSUD-associated mutations in other genes (reviewed in Strauss et al, 2020).
Functional studies have been performed on only a handful of DBT mutations (Indo et al, 1987; Indo et al, 1988; Mitsubuchi et al, 1991; Tsuruta et al, 1998); however modelling based on the solved NMR structure suggests that many of these mutations may affect subunit association and the hydrophobic core, thus destabilizing the overall assembly and activity of the BCKDH complex (Chang et al, 2002; Mitsubuchi et al, 1991; Tsuruta et al, 1998; Fisher et al, 1991). The following mutations in DBT are classified as "pathogenic" or "likely pathogenic" in ClinVar, with the exception of S399C which has no pathogenicity designated. The mutations are annotated either as members or candidates of the disease set based on levels of experimental evidence available:

member:

I98M: Tsuruta et al, 1998; Indo et al, 1987

candidates:

P276C: Fisher et al, 1991

S399C: Ali and Ngu, 2018

K313_Y338del: Mitsubuchi et al, 1991.
Literature References
PubMed ID Title Journal Year
1847055 A 17-bp insertion and a Phe215----Cys missense mutation in the dihydrolipoyl transacylase (E2) mRNA from a thiamine-responsive maple syrup urine disease patient WG-34

Fisher, CW, Lau, KS, Fisher, CR, Wynn, RM, Cox, RP, Chuang, DT

Biochem Biophys Res Commun 1991
30228974 Fourteen new mutations of BCKDHA, BCKDHB and DBT genes associated with maple syrup urine disease (MSUD) in Malaysian population

Ali, EZ, Ngu, LH

Mol Genet Metab Rep 2018
3597778 Altered kinetic properties of the branched-chain alpha-keto acid dehydrogenase complex due to mutation of the beta-subunit of the branched-chain alpha-keto acid decarboxylase (E1) component in lymphoblastoid cells derived from patients with maple syrup urine disease

Indo, Y, Kitano, A, Endo, F, Akaboshi, I, Matsuda, I

J Clin Invest 1987
20301495 Maple Syrup Urine Disease

Strauss, KA, Puffenberger, EG, Carson, VJ

2006
2010537 Maple syrup urine disease caused by a partial deletion in the inner E2 core domain of the branched chain alpha-keto acid dehydrogenase complex due to aberrant splicing. A single base deletion at a 5'-splice donor site of an intron of the E2 gene disrupts the consensus sequence in this region

Mitsubuchi, H, Nobukuni, Y, Akaboshi, I, Indo, Y, Endo, F, Matsuda, I

J Clin Invest 1991
31084571 Role of branched-chain amino acid-catabolizing enzymes in intertissue signaling, metabolic remodeling, and energy homeostasis

Biswas, D, Duffley, L, Pulinilkunnil, T

FASEB J 2019
11839747 Solution structure and dynamics of the lipoic acid-bearing domain of human mitochondrial branched-chain alpha-keto acid dehydrogenase complex

Chang, CF, Chou, HT, Chuang, JL, Chuang, DT, Huang, TH

J Biol Chem 2002
9239422 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

Chuang, JL, Cox, RP, Chuang, DT

J Clin Invest 1997
3417306 Maple syrup urine disease: a possible biochemical basis for the clinical heterogeneity

Indo, Y, Akaboshi, I, Nobukuni, Y, Endo, F, Matsuda, I

Hum Genet 1988
9621512 Molecular basis of intermittent maple syrup urine disease: novel mutations in the E2 gene of the branched-chain alpha-keto acid dehydrogenase complex

Tsuruta, M, Mitsubuchi, H, Mardy, S, Miura, Y, Hayashida, Y, Kinugasa, A, Ishitsu, T, Matsuda, I, Indo, Y

J Hum Genet 1998
Participants
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as an event of
Catalyst Activity

acyltransferase activity, transferring groups other than amino-acyl groups of DBT mutant-BCKDH [mitochondrial matrix]

Physical Entity
DBT mutant-BCKDH [mitochondrial matrix] (Homo sapiens)
Activity
acyltransferase activity, transferring groups other than amino-acyl groups (GO:0016747)
Normal reaction
DBT transfers BCAA to CoA (Homo sapiens)
Functional status

Loss of function of DBT mutant-BCKDH [mitochondrial matrix]

Normal Entity
Disease Entity
Status
Disease
Name Identifier Synonyms
maple syrup urine disease DOID:9269 dihydrolipoamide dehydrogenase deficiency
Cross References
Mondo
Authored
Rothfels, K  (2024-07-29)
Reviewed
D'Eustachio, P  (2024-08-18)
Created
Rothfels, K  (2024-03-08)
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