The molecular basis of human 3-methylcrotonyl-CoA carboxylase deficiency

Isolated biotin-resistant 3-methylcrotonyl-CoA carboxylase (MCC) deficiency is an autosomal recessive disorder of leucine catabolism that appears to b e the most frequent organic aciduria detected in tandem mass spectrometry-b ased neonatal screening programs. The phenotype is variable, ranging from n eonatal onset with severe neurological involvement to asymptomatic adults. MCC is a heteromeric mitochondrial enzyme composed of biotin-containing a s ubunits and smaller beta subunits. Here, we report cloning of MCCA and MCCB cDNAs and the organization of their structural genes. We show that a serie s of 14 MCC-deficient probands defines two complementation groups, CG1 and 2, resulting from mutations in MCCB and MCCA, respectively. We identify fiv e MCCA and nine MCCB mutant alleles and show that missense mutations in eac h result in loss of function.