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Disease-causing missense mutations affect enzymatic activity, stability and oligomerization of glutaryl-CoA dehydrogenase (GCDH)

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Disease-causing missense mutations affect enzymatic activity, stability and oligomerization of glutaryl-CoA dehydrogenase (GCDH). / Keyser, Britta; Mühlhausen, Chris; Dickmanns, Achim; Christensen, Ernst; Muschol, Nicole; Ullrich, Kurt; Braulke, Thomas.

in: HUM MOL GENET, Jahrgang 17, Nr. 24, 24, 15.12.2008, S. 3854-3863.

Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung

Harvard

Keyser, B, Mühlhausen, C, Dickmanns, A, Christensen, E, Muschol, N, Ullrich, K & Braulke, T 2008, 'Disease-causing missense mutations affect enzymatic activity, stability and oligomerization of glutaryl-CoA dehydrogenase (GCDH)', HUM MOL GENET, Jg. 17, Nr. 24, 24, S. 3854-3863. https://doi.org/10.1093/hmg/ddn284

APA

Keyser, B., Mühlhausen, C., Dickmanns, A., Christensen, E., Muschol, N., Ullrich, K., & Braulke, T. (2008). Disease-causing missense mutations affect enzymatic activity, stability and oligomerization of glutaryl-CoA dehydrogenase (GCDH). HUM MOL GENET, 17(24), 3854-3863. [24]. https://doi.org/10.1093/hmg/ddn284

Vancouver

Keyser B, Mühlhausen C, Dickmanns A, Christensen E, Muschol N, Ullrich K et al. Disease-causing missense mutations affect enzymatic activity, stability and oligomerization of glutaryl-CoA dehydrogenase (GCDH). HUM MOL GENET. 2008 Dez 15;17(24):3854-3863. 24. https://doi.org/10.1093/hmg/ddn284

Bibtex

@article{7eea1e19a15546e09a031afbc3031cc9,
title = "Disease-causing missense mutations affect enzymatic activity, stability and oligomerization of glutaryl-CoA dehydrogenase (GCDH)",
abstract = "Glutaric aciduria type 1 (GA1) is an autosomal recessive neurometabolic disorder caused by mutations in the glutaryl-CoA dehydrogenase gene (GCDH), leading to an accumulation and high excretion of glutaric acid and 3-hydroxyglutaric acid. Considerable variation in severity of the clinical phenotype is observed with no correlation to the genotype. We report here for the first time on expression studies of four missense mutations c.412A > G (p.Arg138Gly), c.787A > G (p.Met263Val), c.1204C > T (p.Arg402Trp) and c.1240G > A (p.Glu414Lys) identified in GA1 patients in mammalian cells. Biochemical analyses revealed that all mutants were enzymatically inactive with the exception of p.Met263Val which showed 10% activity of the expressed wild-type enzyme. Western blot and pulse-chase analyses demonstrated that the amount of expressed p.Arg402Trp protein was significantly reduced compared with cells expressing wild-type protein which was due to rapid intramitochondrial degradation. Upon cross-linkage the formation of homotetrameric GCDH was strongly impaired in p.Met263Val and p.Arg402Trp mutants. In addition, GCDH appears to interact with distinct heterologous polypeptides to form novel 97, 130 and 200 kDa GCDH complexes. Molecular modeling of mutant GCDH suggests that Met263 at the surface of the GCDH protein might be part of the contact interface to interacting proteins. These results indicate that reduced intramitochondrial stability as well as the impaired formation of homo- and heteromeric GCDH complexes can underlie GA1.",
keywords = "Amino Acid Metabolism, Inborn Errors/enzymology, Amino Acid Substitution/genetics, Animals, Catalysis, Cell Line, Cricetinae, Enzyme Activation/genetics, Enzyme Stability/genetics, Gene Expression Regulation/genetics, Genes, Recessive, Glutarates/metabolism, Glutaryl-CoA Dehydrogenase/chemistry, Humans, Mitochondrial Proteins/chemistry, Mutation, Missense/genetics, Protein Structure, Quaternary/genetics",
author = "Britta Keyser and Chris M{\"u}hlhausen and Achim Dickmanns and Ernst Christensen and Nicole Muschol and Kurt Ullrich and Thomas Braulke",
year = "2008",
month = dec,
day = "15",
doi = "10.1093/hmg/ddn284",
language = "English",
volume = "17",
pages = "3854--3863",
journal = "HUM MOL GENET",
issn = "0964-6906",
publisher = "Oxford University Press",
number = "24",

}

RIS

TY - JOUR

T1 - Disease-causing missense mutations affect enzymatic activity, stability and oligomerization of glutaryl-CoA dehydrogenase (GCDH)

AU - Keyser, Britta

AU - Mühlhausen, Chris

AU - Dickmanns, Achim

AU - Christensen, Ernst

AU - Muschol, Nicole

AU - Ullrich, Kurt

AU - Braulke, Thomas

PY - 2008/12/15

Y1 - 2008/12/15

N2 - Glutaric aciduria type 1 (GA1) is an autosomal recessive neurometabolic disorder caused by mutations in the glutaryl-CoA dehydrogenase gene (GCDH), leading to an accumulation and high excretion of glutaric acid and 3-hydroxyglutaric acid. Considerable variation in severity of the clinical phenotype is observed with no correlation to the genotype. We report here for the first time on expression studies of four missense mutations c.412A > G (p.Arg138Gly), c.787A > G (p.Met263Val), c.1204C > T (p.Arg402Trp) and c.1240G > A (p.Glu414Lys) identified in GA1 patients in mammalian cells. Biochemical analyses revealed that all mutants were enzymatically inactive with the exception of p.Met263Val which showed 10% activity of the expressed wild-type enzyme. Western blot and pulse-chase analyses demonstrated that the amount of expressed p.Arg402Trp protein was significantly reduced compared with cells expressing wild-type protein which was due to rapid intramitochondrial degradation. Upon cross-linkage the formation of homotetrameric GCDH was strongly impaired in p.Met263Val and p.Arg402Trp mutants. In addition, GCDH appears to interact with distinct heterologous polypeptides to form novel 97, 130 and 200 kDa GCDH complexes. Molecular modeling of mutant GCDH suggests that Met263 at the surface of the GCDH protein might be part of the contact interface to interacting proteins. These results indicate that reduced intramitochondrial stability as well as the impaired formation of homo- and heteromeric GCDH complexes can underlie GA1.

AB - Glutaric aciduria type 1 (GA1) is an autosomal recessive neurometabolic disorder caused by mutations in the glutaryl-CoA dehydrogenase gene (GCDH), leading to an accumulation and high excretion of glutaric acid and 3-hydroxyglutaric acid. Considerable variation in severity of the clinical phenotype is observed with no correlation to the genotype. We report here for the first time on expression studies of four missense mutations c.412A > G (p.Arg138Gly), c.787A > G (p.Met263Val), c.1204C > T (p.Arg402Trp) and c.1240G > A (p.Glu414Lys) identified in GA1 patients in mammalian cells. Biochemical analyses revealed that all mutants were enzymatically inactive with the exception of p.Met263Val which showed 10% activity of the expressed wild-type enzyme. Western blot and pulse-chase analyses demonstrated that the amount of expressed p.Arg402Trp protein was significantly reduced compared with cells expressing wild-type protein which was due to rapid intramitochondrial degradation. Upon cross-linkage the formation of homotetrameric GCDH was strongly impaired in p.Met263Val and p.Arg402Trp mutants. In addition, GCDH appears to interact with distinct heterologous polypeptides to form novel 97, 130 and 200 kDa GCDH complexes. Molecular modeling of mutant GCDH suggests that Met263 at the surface of the GCDH protein might be part of the contact interface to interacting proteins. These results indicate that reduced intramitochondrial stability as well as the impaired formation of homo- and heteromeric GCDH complexes can underlie GA1.

KW - Amino Acid Metabolism, Inborn Errors/enzymology

KW - Amino Acid Substitution/genetics

KW - Animals

KW - Catalysis

KW - Cell Line

KW - Cricetinae

KW - Enzyme Activation/genetics

KW - Enzyme Stability/genetics

KW - Gene Expression Regulation/genetics

KW - Genes, Recessive

KW - Glutarates/metabolism

KW - Glutaryl-CoA Dehydrogenase/chemistry

KW - Humans

KW - Mitochondrial Proteins/chemistry

KW - Mutation, Missense/genetics

KW - Protein Structure, Quaternary/genetics

U2 - 10.1093/hmg/ddn284

DO - 10.1093/hmg/ddn284

M3 - SCORING: Journal article

C2 - 18775954

VL - 17

SP - 3854

EP - 3863

JO - HUM MOL GENET

JF - HUM MOL GENET

SN - 0964-6906

IS - 24

M1 - 24

ER -