Header

UZH-Logo

Maintenance Infos

Molecular mechanism of dominant expression in 3-methylcrotonyl-CoA carboxylase deficiency


Baumgartner, M R (2005). Molecular mechanism of dominant expression in 3-methylcrotonyl-CoA carboxylase deficiency. Journal of Inherited Metabolic Disease, 28(3):301-309.

Abstract

Summary: Most enzyme deficiencies in humans are inherited as autosomal recessive traits. The term dominant negative is applied to mutant alleles in which a mutant protein interferes in one way or another with the function of the normal protein being produced from the wild-type allele in a heterozygote. Such a dominant negative effect usually involves homomeric or heteromeric proteins. 3-Methylcrotonyl-CoA carboxylase (MCC) is a heteromeric mitochondrial enzyme comprised of biotin containing MCCα subunits and smaller MCCβ subunits, encoded by the genes MCCA and MCCB, respectively. Mutations in these genes cause isolated MCC deficiency, an autosomal recessive disorder with a variable phenotype ranging from severe neonatal to asymptomatic adult forms. Patients with MCC deficiency have a characteristic organic aciduria with greatly increased excretion of 3-hydroxyisovaleric acid (3-HIVA) and 3-methylcrotonyl-glycine (3-MCG). Here, two patients with elevated excretion of 3-MCG and 3-HIVA and partial deficiency of MCC are discussed, one of them with severe neurological symptoms. Both showed evidence of biotin responsiveness and were heterozygous for the missense mutation MCCA-R385S. Evidence is presented that MCCA-R385S is a dominant negative allele leading to biochemical abnormalities and clinical symptoms in heterozygous individuals and that it is responsive to pharmacological doses of biotin in vivo

Abstract

Summary: Most enzyme deficiencies in humans are inherited as autosomal recessive traits. The term dominant negative is applied to mutant alleles in which a mutant protein interferes in one way or another with the function of the normal protein being produced from the wild-type allele in a heterozygote. Such a dominant negative effect usually involves homomeric or heteromeric proteins. 3-Methylcrotonyl-CoA carboxylase (MCC) is a heteromeric mitochondrial enzyme comprised of biotin containing MCCα subunits and smaller MCCβ subunits, encoded by the genes MCCA and MCCB, respectively. Mutations in these genes cause isolated MCC deficiency, an autosomal recessive disorder with a variable phenotype ranging from severe neonatal to asymptomatic adult forms. Patients with MCC deficiency have a characteristic organic aciduria with greatly increased excretion of 3-hydroxyisovaleric acid (3-HIVA) and 3-methylcrotonyl-glycine (3-MCG). Here, two patients with elevated excretion of 3-MCG and 3-HIVA and partial deficiency of MCC are discussed, one of them with severe neurological symptoms. Both showed evidence of biotin responsiveness and were heterozygous for the missense mutation MCCA-R385S. Evidence is presented that MCCA-R385S is a dominant negative allele leading to biochemical abnormalities and clinical symptoms in heterozygous individuals and that it is responsive to pharmacological doses of biotin in vivo

Statistics

Citations

Dimensions.ai Metrics
10 citations in Web of Science®
9 citations in Scopus®
Google Scholar™

Altmetrics

Downloads

16 downloads since deposited on 23 Oct 2018
9 downloads since 12 months
Detailed statistics

Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:National licences > 142-005
Dewey Decimal Classification:610 Medicine & health
Scopus Subject Areas:Life Sciences > Genetics
Health Sciences > Genetics (clinical)
Language:English
Date:1 May 2005
Deposited On:23 Oct 2018 16:00
Last Modified:31 Jul 2020 02:37
Publisher:Springer
ISSN:0141-8955
OA Status:Green
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1007/s10545-005-7054-3
Related URLs:https://www.swissbib.ch/Search/Results?lookfor=nationallicencespringer101007s1054500570543 (Library Catalogue)

Download

Green Open Access

Download PDF  'Molecular mechanism of dominant expression in 3-methylcrotonyl-CoA carboxylase deficiency'.
Preview
Content: Published Version
Language: English
Filetype: PDF (Nationallizenz 142-005)
Size: 151kB
View at publisher