The molecular basis of human 3-methylcrotonyl-CoA carboxylase deficiency
Matthias R. Baumgartner, Shlomo Almashanu, Terttu Suormala, Cassandra Obie, Robert N. Cole, Seymour Packman, E. Regula Baumgartner, David Valle
Matthias R. Baumgartner, Shlomo Almashanu, Terttu Suormala, Cassandra Obie, Robert N. Cole, Seymour Packman, E. Regula Baumgartner, David Valle
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The molecular basis of human 3-methylcrotonyl-CoA carboxylase deficiency

Abstract

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

Authors

Matthias R. Baumgartner, Shlomo Almashanu, Terttu Suormala, Cassandra Obie, Robert N. Cole, Seymour Packman, E. Regula Baumgartner, David Valle

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Sequence alignment of human MCCα and MCCβ with orthologs from mouse and ...
Sequence alignment of human MCCα and MCCβ with orthologs from mouse and A. thaliana. Amino acids identical to the human sequence are highlighted. Missense mutations identified in MCC-deficient patients are indicated above with the substituted amino acid. Potential cleavage sites for the NH2-terminal mitochondrial leader sequences are indicated by vertical arrowheads. (a) Sequence alignment of human, mouse, and A. thaliana MCCα. The predicted ATP-binding site in the NH2-terminal biotin carboxylation domain and the predicted COOH-terminal biotin carboxyl carrier domain are indicated by solid and dashed over-lines, respectively. The arrow indicates the lysine residue that links covalently to biotin (biocytin). The residues marked with an asterisk within the biotin carboxylation domain are thought to play an important role in catalysis (36, 37). (b) Sequence alignment of human and A. thaliana MCCβ. The putative 3-methylcrotonyl-CoA binding domain is indicated by a solid over-line.