IVD mutants don't synthesize beta-methylcrotonyl-CoA

Stable Identifier
R-HSA-9914837
Type
Reaction [transition]
Species
Homo sapiens
Compartment
mitochondrial matrix
ReviewStatus
5/5
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IVD mutants don't synthesize beta-methylcrotonyl-CoA
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The following mutations in IVD have been identified in patients with varying phenotypic presentations of isovaleric acidemia. Each mutation identified as a member of this disease set have been shown to have significantly decreased or abolished protein levels and/or enzymatic activity (Mohsen et al, 1998; Dercksen et al, 2012; D'Annibale et al, 2021). Mutations annotated as candidates of this disease set are predicted to have compromised function based on structural modeling, predicted changes to physicochemical properties and in silico pathogenetic and stability assays (Zaki et al, 2017). Most of the mutations in this set, both candidates and members, are designated as "pathogenic" or "likely pathogenic" in ClinVar.

Members:
L45P: severely reduced protein expression (Mohsen et al, 1998)

R53P: rapidly degraded; no detectable enzyme activity (Mohsen et al, 1998; D'Annibale et al, 2021)

D72N: no detectable enzyme activity (Mohsen et al, 1998)

G123R: decreased steady state protein levels, almost no detectable enzyme activity (Dercksen et al, 2012)

T239I: reduced protein expression and enzyme activity (D'Annibale et al, 2021)

A314V: mild variant: decreased protein level and activity, but retains some function (Mohsen et al, 1998; D'Annibale et al, 2021)

M332T: reduced protein expression and enzyme activity (D'Annibale et al, 2021)

R340Q: reduced protein expression and enzyme activity (D'Annibale et al, 2021)

C360R: rapidly degraded; no detectable enzyme activity (Mohsen et al, 1998)

V374A: decreased protein stability and activity (Mohsen et al, 1998); R395C: decreased protein stability and activity (Mohsen et al, 1998)

R414L: decreased protein stability and activity (Mohsen et al, 1998; D'Annibale et al, 2021).

Candidates:

I379T: predicted to be pathogenic and destabilizing by 10 out of 12 in silico tools (Zaki et al, 2017)

R398Q: predicted to be pathogenic and destabilizing by 10 out of 12 in silico tools (Zaki et al, 2017)

Y403N: predicted to be pathogenic and destabilizing by 7 out of 12 in silico tools (Zaki et al, 2017).
Literature References
PubMed ID Title Journal Year
34535384 Characterization of variants of uncertain significance in isovaleryl-CoA dehydrogenase identified through newborn screening: An approach for faster analysis

D'Annibale, OM, Koppes, EA, Alodaib, AN, Kochersperger, C, Karunanidhi, A, Mohsen, AW, Vockley, J

Mol Genet Metab 2021
28535199 Genotype-phenotype correlation in patients with isovaleric acidaemia: comparative structural modelling and computational analysis of novel variants

Zaki, OK, Priya Doss C, G, Ali, SA, Murad, GG, Elashi, SA, Ebnou, MSA, Kumar D, T, Khalifa, O, Gamal, R, El Abd, HSA, Nasr, BN, Zayed, H

Hum Mol Genet 2017
22350545 Clinical variability of isovaleric acidemia in a genetically homogeneous population

Dercksen, M, Duran, M, Ijlst, L, Mienie, LJ, Reinecke, CJ, Ruiter, JP, Waterham, HR, Wanders, RJ

J Inherit Metab Dis 2012
9665741 Characterization of molecular defects in isovaleryl-CoA dehydrogenase in patients with isovaleric acidemia

Mohsen, AW, Anderson, BD, Volchenboum, SL, Battaile, KP, Tiffany, K, Roberts, D, Kim, JJ, Vockley, J

Biochemistry 1998
Participants
Input
Participates
as an event of
Catalyst Activity

3-methylbutanoyl-CoA dehydrogenase activity of mutant IVD tetramer [mitochondrial matrix]

Physical Entity
mutant IVD tetramer [mitochondrial matrix] (Homo sapiens)
Activity
3-methylbutanoyl-CoA dehydrogenase activity (GO:0008470)
Normal reaction
isovaleryl-CoA + FAD => beta-methylcrotonyl-CoA + FADH2 (Homo sapiens)
Functional status

Loss of function of mutant IVD tetramer [mitochondrial matrix]

Normal Entity
Disease Entity
Status
Disease
Name Identifier Synonyms
isovaleric acidemia DOID:14753 Isovaleryl-CoA dehydrogenase deficiency, isovaleric acid CoA dehydrogenase deficiency, isovaleric aciduria
Cross References
Mondo
Authored
Rothfels, K  (2024-07-29)
Reviewed
D'Eustachio, P  (2024-08-18)
Created
Rothfels, K  (2024-06-27)
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