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Mutations participating in interallelic complementation in propionic acidemia

R A Gravel1, B R Akerman, A M Lamhonwah

  • 1McGill University-Montreal Children's Hospital Research Institute, Quebec, Canada.

American Journal of Human Genetics
|July 1, 1994
PubMed
Summary

Interallelic complementation in propionic acidemia arises from specific mutations in the propionyl-CoA carboxylase beta-subunit gene (PCCB). These mutations restore enzyme function by allowing interacting beta-subunits to form a functional propionyl-CoA carboxylase complex.

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Area of Science:

  • Biochemistry
  • Genetics
  • Metabolic Disorders

Background:

  • Propionic acidemia is a rare, autosomal recessive disorder caused by deficiency of propionyl-CoA carboxylase (PCC).
  • Cell fusion studies identified two complementation groups (pccA, pccB) linked to PCCA and PCCB genes, respectively.
  • The pccB group includes subgroups (pccB, pccC) suggesting interallelic complementation within the PCCB gene.

Purpose of the Study:

  • To identify specific mutations in propionic acidemia cell lines (pccB, pccC, pccBC).
  • To determine which alleles participate in interallelic complementation within the PCCB gene.
  • To elucidate the mechanism of interallelic complementation in propionyl-CoA carboxylase deficiency.

Main Methods:

  • Mutation analysis in patient-derived cell lines.

Related Experiment Videos

  • Cell fusion experiments to assess complementation.
  • Sequence homology analysis with bacterial transcarboxylase.

    • Main Results:

    • Identified specific mutations (Pro228Leu, dupKICK140-143, Arg410Trp, delta Ile408, Ins.Del) in pccB and pccC cell lines.
    • Determined that Pro228Leu and dupKICK140-143 are complementing alleles in pccB lines.
    • Arg410Trp is a complementing allele in a pccC line, while Ins.Del at codon 407 fails to complement homozygously.

    Conclusions:

    • Interallelic complementation in propionic acidemia results from mutations in PCCB beta-subunit domains that interact.
    • These interactions between beta-subunits restore the enzymatic function of the propionyl-CoA carboxylase heteromer.
    • The pccC domain, involving residues Ile408 and Arg410, may be critical for propionyl-CoA binding.