title: Amerindian pyruvate carboxylase deficiency is associated with two distinct missense mutations.
abstract: We characterized the pyruvate carboxylase (PC) gene by PCR amplification, subcloning, and sequencing. The coding region has 19 exons and 18 introns spanning approximately 16 kb of genomic DNA. Screening both the cDNA and the gene of individuals with the simple A form of PC deficiency revealed an 1828G-->A missense mutation in 11 Ojibwa and 2 Cree patients and a 2229G-->T transversion mutation in 2 brothers of Micmac origin. Carrier frequency may be as high as 1/10 in some groupings. The two point mutations are located in a region of homology conserved among yeast, rat, and human PC, in the vicinity of the carboxylation domain of the enzyme. These data provide the first characterization of the human PC gene structure, the identification of common pathogenic mutations, and the demonstration of a founder effect in the Ojibwa and Cree patients.
authors.affiliation: Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada.
authors.forename: M A
authors.initials: MA
authors.lastname: Carbone
authors.forename: N
authors.initials: N
authors.lastname: MacKay
authors.forename: M
authors.initials: M
authors.lastname: Ling
authors.forename: D E
authors.initials: DE
authors.lastname: Cole
authors.forename: C
authors.initials: C
authors.lastname: Douglas
authors.forename: B
authors.initials: B
authors.lastname: Rigat
authors.forename: A
authors.initials: A
authors.lastname: Feigenbaum
authors.forename: J T
authors.initials: JT
authors.lastname: Clarke
authors.forename: J C
authors.initials: JC
authors.lastname: Haworth
authors.forename: C R
authors.initials: CR
authors.lastname: Greenberg
authors.forename: L
authors.initials: L
authors.lastname: Seargeant
authors.forename: B H
authors.initials: BH
authors.lastname: Robinson
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000201:enzymology; D002170:Canada; D002460:Cell Line; D004252:DNA Mutational Analysis; D005091:Exons; D006801:Humans; D007198:Indians, North American / Q000235:genetics*; D007438:Introns; D008099:Liver / Q000201:enzymology; D008969:Molecular Sequence Data; D017354:Point Mutation; D015324:Pyruvate Carboxylase Deficiency Disease / Q000235:genetics*; D051381:Rats; D017386:Sequence Homology, Amino Acid