The molecular basis of 3-methylcrotonylglycinuria, a disorder of leucine catabolism

Am J Hum Genet. 2001 Feb;68(2):334-46. doi: 10.1086/318202. Epub 2001 Jan 17.

Abstract

3-Methylcrotonylglycinuria is an inborn error of leucine catabolism and has a recessive pattern of inheritance that results from the deficiency of 3-methylcrotonyl-CoA carboxylase (MCC). The introduction of tandem mass spectrometry in newborn screening has revealed an unexpectedly high incidence of this disorder, which, in certain areas, appears to be the most frequent organic aciduria. MCC, an heteromeric enzyme consisting of alpha (biotin-containing) and beta subunits, is the only one of the four biotin-dependent carboxylases known in humans that has genes that have not yet been characterized, precluding molecular studies of this disease. Here we report the characterization, at the genomic level and at the cDNA level, of both the MCCA gene and the MCCB gene, encoding the MCC alpha and MCC beta subunits, respectively. The 19-exon MCCA gene maps to 3q25-27 and encodes a 725-residue protein with a biotin attachment site; the 17-exon MCCB gene maps to 5q12-q13 and encodes a 563-residue polypeptide. We show that disease-causing mutations can be classified into two complementation groups, denoted "CGA" and "CGB." We detected two MCCA missense mutations in CGA patients, one of which leads to absence of biotinylated MCC alpha. Two MCCB missense mutations and one splicing defect mutation leading to early MCC beta truncation were found in CGB patients. A fourth MCCB mutation also leading to early MCC beta truncation was found in two nonclassified patients. A fungal model carrying an mccA null allele has been constructed and was used to demonstrate, in vivo, the involvement of MCC in leucine catabolism. These results establish that 3-methylcrotonylglycinuria results from loss-of-function mutations in the genes encoding the alpha and beta subunits of MCC and complete the genetic characterization of the four human biotin-dependent carboxylases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Amino Acid Metabolism, Inborn Errors / enzymology
  • Amino Acid Metabolism, Inborn Errors / genetics*
  • Amino Acid Metabolism, Inborn Errors / pathology
  • Amino Acid Sequence
  • Aspergillus nidulans / drug effects
  • Aspergillus nidulans / genetics
  • Aspergillus nidulans / growth & development
  • Base Sequence
  • Blotting, Northern
  • Carbon-Carbon Ligases / genetics*
  • Carbon-Carbon Ligases / metabolism
  • Child, Preschool
  • Chromosome Mapping
  • Chromosomes, Human, Pair 3 / genetics
  • Chromosomes, Human, Pair 5 / genetics
  • DNA / chemistry
  • DNA / genetics
  • DNA Mutational Analysis
  • DNA, Complementary / chemistry
  • DNA, Complementary / genetics
  • Exons
  • Female
  • Gene Expression Regulation, Enzymologic
  • Genes / genetics
  • Humans
  • In Situ Hybridization, Fluorescence
  • Infant
  • Introns
  • Isoenzymes / genetics
  • Isoenzymes / metabolism
  • Leucine / metabolism*
  • Leucine / pharmacology
  • Molecular Sequence Data
  • Mutation
  • Protein Subunits
  • RNA / genetics
  • RNA / metabolism
  • Radiation Hybrid Mapping
  • Sequence Analysis, DNA
  • Tissue Distribution
  • Transcription, Genetic

Substances

  • DNA, Complementary
  • Isoenzymes
  • Protein Subunits
  • RNA
  • DNA
  • Carbon-Carbon Ligases
  • methylcrotonoyl-CoA carboxylase
  • Leucine

Associated data

  • GENBANK/AF310971
  • GENBANK/AF310972
  • OMIM/210200