Loss-of-function DLD mutants don't dehydrogenate dihydrolipoyl DBT

Stable Identifier
R-HSA-9907572
Type
Reaction [transition]
Species
Homo sapiens
Compartment
mitochondrial matrix
ReviewStatus
5/5
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Loss-of-function DLD mutants don't dehydrogenate dihydrolipoyl DBT
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Loss-of-function mutations in DLD are associated with Maple Syrup Urine Disease 3 (MSUD3), also known as DLD deficiency. Unlike MSUD1A, B and 2, which are biochemically indistinguishable, MSUD3 is clinically distinct as a result of the impact of the mutations in DLD on all three multiprotein complexes in which it takes part (reviewed in Strauss et al, 2020; Quinonez and Thoene, 2021). Mutations in DLD often arise as compound heterozygotes with a range of clinical features and severities that are not mappable in a straightforward way to the reduction in DLD enzymatic activity in vitro (Quinonez et al, 2013; Shany et al, 1999; Cameron et al, 2006; reviewed in Quinonez and Thoene, 2021). Due to this uncertainty, the following DLD mutations are annotated as candidates on the basis of showing decreased DLD activity and/or decreased DLD protein levels and/or decreased overall BCKDH activity and/or elevated rates of branched-chain amino acids in the plasma:
I47T (Cameron et al, 2006); G229C (Cameron et al, 2006; Shaag et al, 1999); M361V (Cerna et al, 2001); E375K (Cameron et al, 2006; Cerna et al, 2001; Hong et al, 1997); I393T (Grafakou et al, 2003); D479V (Shany et al, 1999); R495 G (Hong et al, 1996; Brautigam et al, 2006). Each of these mutations is designated "pathogenic" or "likely pathogenic" in ClinVar.
Literature References
PubMed ID Title Journal Year
16770810 Novel mutations in dihydrolipoamide dehydrogenase deficiency in two cousins with borderline-normal PDH complex activity

Cameron, JM, Levandovskiy, V, MacKay, N, Raiman, J, Renaud, DL, Clarke, JT, Feigenbaum, A, Elpeleg, O, Robinson, BH

Am J Med Genet A 2006
23290025 Leigh syndrome in a girl with a novel DLD mutation causing E3 deficiency

Quinonez, SC, Leber, SM, Martin, DM, Thoene, JG, Bedoyan, JK

Pediatr Neurol 2013
10448086 Lipoamide dehydrogenase deficiency due to a novel mutation in the interface domain

Shany, E, Saada, A, Landau, D, Shaag, A, Hershkovitz, E, Elpeleg, ON

Biochem Biophys Res Commun 1999
16442803 Structural insight into interactions between dihydrolipoamide dehydrogenase (E3) and E3 binding protein of human pyruvate dehydrogenase complex

Brautigam, CA, Wynn, RM, Chuang, JL, Machius, M, Tomchick, DR, Chuang, DT

Structure 2006
25032271 Dihydrolipoamide Dehydrogenase Deficiency

Quinonez, SC, Thoene, JG

2014
20301495 Maple Syrup Urine Disease

Strauss, KA, Puffenberger, EG, Carson, VJ

2006
8968745 Identification of two mutations in a compound heterozygous child with dihydrolipoamide dehydrogenase deficiency

Hong, YS, Kerr, DS, Craigen, WJ, Tan, J, Pan, Y, Lusk, M, Patel, MS

Hum Mol Genet 1996
9540846 Deficiency of dihydrolipoamide dehydrogenase due to two mutant alleles (E340K and G101del). Analysis of a family and prenatal testing

Hong, YS, Kerr, DS, Liu, TC, Lusk, M, Powell, BR, Patel, MS

Biochim Biophys Acta 1997
11687750 Novel mutations in a boy with dihydrolipoamide dehydrogenase deficiency

Cerna, L, Wenchich, L, Hansikova, H, Kmoch, S, Peskova, K, Chrastina, P, Brynda, J, Zeman, J

Med Sci Monit 2001
Participants
Input
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as an event of
Catalyst Activity

dihydrolipoyl dehydrogenase (NADH) activity of DLD mutant-BCKDH [mitochondrial matrix]

Physical Entity
DLD mutant-BCKDH [mitochondrial matrix] (Homo sapiens)
Activity
dihydrolipoyl dehydrogenase (NADH) activity (GO:0004148)
Normal reaction
DLD dimer dehydrogenates dihydrolipoyl (Homo sapiens)
Functional status

Loss of function of DLD 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  (2024-04-12)
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