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Molecular mechanism of dominant expression in 3‐methylcrotonyl‐CoA carboxylase deficiency
Author(s) -
Baumgartner M. R.
Publication year - 2005
Publication title -
journal of inherited metabolic disease
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.462
H-Index - 102
eISSN - 1573-2665
pISSN - 0141-8955
DOI - 10.1007/s10545-005-7054-3
Subject(s) - missense mutation , heterozygote advantage , biology , mutant , allele , compound heterozygosity , genetics , phenotype , mutation , enzyme , gene , microbiology and biotechnology , endocrinology , biochemistry
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 .