Human Molecular Genetics, 2001, Vol. 10, No. 12 1299-1306
© 2001 Oxford University Press
Cloning of the human MCCA and MCCB genes and mutations therein reveal the molecular cause of 3-methylcrotonyl-CoA: carboxylase deficiency
Ludwig-Maximilians-University, Dr von Hauner Children’s Hospital, Department of Clinical Chemistry and Biochemical Genetics, Lindwurmstrasse 4, D-80337 Munich, Germany, 1University of California, San Diego, Department of Pediatrics, Biochemical Genetics Laboratory, 220 Dickinson Street, CA 92103, USA and 2University of Münster, Klinik und Poliklinik für Kinderheilkunde, Albert-Schweitzer-Strasse 33, D-48149 Münster, Germany
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 
- and ß-subunits of human MCC. The 2580 bp MCCA cDNA encodes the 725 amino acid biotin-containing -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 ß-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.
+ These authors contributed equally to this work
To whom correspondence should be addressed. Tel: +49 89 5160 2805; Fax: +49 89 5160 3320; Email: holzinger@kk-i.med.uni-muenchen.de
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