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Cloning of the human MCCA and MCCB genes and mutations therein reveal the molecular cause of 3-methylcrotonyl-CoA: carboxylase deficiency

Holzinger, A, Roschinger, W, Lagler, F, Mayerhofer, PU, Lichtner, P, Kattenfeld, T, Thuy, LP, Nyhan, WL, Koch, HG, Muntau, AC and Roscher, AA (2001) Cloning of the human MCCA and MCCB genes and mutations therein reveal the molecular cause of 3-methylcrotonyl-CoA: carboxylase deficiency Hum Mol Genet, 10. pp. 1299-1306.

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Abstract

3-Methylcrotonyl-CoA: carboxylase (EC 6.4.1.4; MCC) deficiency is an inborn error of the leucine degradation pathway (MIM *210200) characterized by increased urinary excretion of 3-hydroxyisovaleric acid and 3-methylcrotonylglycine. The clinical phenotypes are highly variable ranging from asymptomatic to profound metabolic acidosis and death in infancy. Sequence similarity with Glycine max and Arabidopsis thaliana genes encoding the two subunits of MCC permitted us to clone the cDNAs encoding the alpha- and beta-subunits of human MCC. The 2580 bp MCCA cDNA encodes the 725 amino acid biotin-containing alpha-subunit. The MCCA gene is located on chromosome 3q26-q28 and consists of 19 exons. The 2304 bp MCCB cDNA encodes the non-biotin-containing beta-subunit of 563 amino acids. The MCCB gene is located on chromosome 5q13 and consists of 17 exons. We have sequenced both genes in four patients with isolated biotin-unresponsive deficiency of MCC. In two of them we found mutations in the MCCA gene. Compound heterozygosity for a missense mutation (S535F) and a nonsense mutation (V694X) were identified in one patient. One heterozygous mutation (S535F) was found in another patient. The remaining two patients had mutations in the MCCB gene. One consanguineous patient was homozygous for a missense mutation (R268T). In the other we identified a missense mutation in one allele (E99Q) and allelic loss of the other. Mutations were correlated with an almost total lack of enzyme activity in fibroblasts. These data provide evidence that human MCC deficiency is caused by mutations in either the MCCA or MCCB gene.

Item Type: Article
Authors :
NameEmailORCID
Holzinger, AUNSPECIFIEDUNSPECIFIED
Roschinger, WUNSPECIFIEDUNSPECIFIED
Lagler, FUNSPECIFIEDUNSPECIFIED
Mayerhofer, PUp.mayerhofer@surrey.ac.ukUNSPECIFIED
Lichtner, PUNSPECIFIEDUNSPECIFIED
Kattenfeld, TUNSPECIFIEDUNSPECIFIED
Thuy, LPUNSPECIFIEDUNSPECIFIED
Nyhan, WLUNSPECIFIEDUNSPECIFIED
Koch, HGUNSPECIFIEDUNSPECIFIED
Muntau, ACUNSPECIFIEDUNSPECIFIED
Roscher, AAUNSPECIFIEDUNSPECIFIED
Date : 2001
Uncontrolled Keywords : Carbon-Carbon Ligases/chemistry/*deficiency/*genetics Child *Chromosomes, Human, Pair 3 *Chromosomes, Human, Pair 5 Cloning, Molecular DNA Mutational Analysis DNA, Complementary Exons Humans In Situ Hybridization, Fluorescence Infant Male Molecular Sequence Data *Mutation
Related URLs :
Depositing User : Symplectic Elements
Date Deposited : 17 May 2017 10:42
Last Modified : 17 May 2017 14:51
URI: http://epubs.surrey.ac.uk/id/eprint/828857

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