title: High incidence of propionic acidemia in greenland is due to a prevalent mutation, 1540insCCC, in the gene for the beta-subunit of propionyl CoA carboxylase.
abstract: Propionyl CoA carboxylase (PCC) is a mitochondrial, biotin-dependent enzyme involved in the catabolism of amino acids, odd-chain fatty acids, and other metabolites. PCC consists of two subunits, alpha and beta, encoded by the PCCA and PCCB genes, respectively. Inherited PCC deficiency due to mutations in either gene results in propionic acidemia (PA), an autosomal recessive disease. Surprisingly, PA is highly prevalent among Inuits in Greenland. We have analyzed reverse transcriptase-PCR products of the beta-subunit mRNA, to characterize the responsible mutation(s). A 3-bp insertion, 1540insCCC, was found in homozygous form in three patients and in compound heterozygous form in one patient. The resulting PCC has no measurable activity, and the mutant beta-subunit appears to be very unstable. To test the hypothesis that a common mutation is responsible for PA in the Greenlandic Inuit population, 310 anonymous DNA samples of Inuit origin were screened for 1540insCCC. We found a carrier frequency of 5%, which is very high compared with those of most other autosomal recessive diseases. Analysis of alleles of a very closely linked marker, D3S2453, revealed a high degree of linkage disequilibrium between one specific allele and 1540insCCC, suggesting that this mutation may be a founder mutation.
authors.affiliation: Department of Clinical Genetics, The Juliane Marie Centre, Rigshospitalet, Copenhagen, Denmark.
authors.forename: K
authors.initials: K
authors.lastname: Ravn
authors.forename: M
authors.initials: M
authors.lastname: Chloupkova
authors.forename: E
authors.initials: E
authors.lastname: Christensen
authors.forename: N J
authors.initials: NJ
authors.lastname: Brandt
authors.forename: H
authors.initials: H
authors.lastname: Simonsen
authors.forename: J P
authors.initials: JP
authors.lastname: Kraus
authors.forename: I M
authors.initials: IM
authors.lastname: Nielsen
authors.forename: F
authors.initials: F
authors.lastname: Skovby
authors.forename: M
authors.initials: M
authors.lastname: Schwartz
mesh_terms: D000483:Alleles; D000592:Amino Acid Metabolism, Inborn Errors / Q000201:enzymology / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism*; D002262:Carboxy-Lyases / Q000737:chemistry* / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D004795:Enzyme Stability; D005006:Ethnicity / Q000235:genetics; D005091:Exons / Q000235:genetics; D005347:Fibroblasts / Q000201:enzymology / Q000378:metabolism; D018703:Founder Effect; D005787:Gene Frequency / Q000235:genetics; D005808:Genes, Recessive / Q000235:genetics; D005838:Genotype; D006116:Greenland / Q000453:epidemiology; D006801:Humans; D015994:Incidence; D015810:Linkage Disequilibrium / Q000235:genetics; D043586:Methylmalonyl-CoA Decarboxylase; D016254:Mutagenesis, Insertional / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D011422:Propionates / Q000097:blood*; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D012867:Skin
chemical_list: D011422:Propionates; D012333:RNA, Messenger; D002262:Carboxy-Lyases; D043586:Methylmalonyl-CoA Decarboxylase; C029658:propionic acid