High Incidence of Propionic Acidemia in Greenland Is Due to a Prevalent Mutation, 1540insCCC, in the Gene for the β-Subunit of Propionyl CoA Carboxylase

• Published in: American journal of human genetics Vol. 67; no. 1; pp. 203 - 206
• Main Authors: Ravn, Kirstine, Chloupkova, Maja, Christensen, Ernst, Brandt, Niels Jacob, Simonsen, Henrik, Kraus, Jan P., Nielsen, Inge Merete, Skovby, Flemming, Schwartz, Marianne
• Format: Journal Article
• Language: English
• Published: Chicago, IL Elsevier Inc 01-07-2000; University of Chicago Press; The American Society of Human Genetics
• Subjects: Alleles; Amino Acid Metabolism, Inborn Errors - enzymology; Amino Acid Metabolism, Inborn Errors - epidemiology; Amino Acid Metabolism, Inborn Errors - genetics; Amino Acid Metabolism, Inborn Errors - metabolism; Biological and medical sciences; Carboxy-Lyases - chemistry; Carboxy-Lyases - deficiency; Carboxy-Lyases - genetics; Carboxy-Lyases - metabolism; Cells, Cultured; Enzyme Stability; Errors of metabolism; Ethnic Groups - genetics; Exons - genetics; Fibroblasts - enzymology; Fibroblasts - metabolism; Founder Effect; Gene Frequency - genetics; Genes, Recessive - genetics; Genotype; Greenland - epidemiology; Humans; Incidence; Linkage Disequilibrium - genetics; Medical sciences; Metabolic diseases; Methylmalonyl-CoA Decarboxylase; Miscellaneous hereditary metabolic disorders; Mutagenesis, Insertional - genetics; Mutation - genetics; Propionates - blood; RNA, Messenger - analysis; RNA, Messenger - genetics; Skin; North America; Greenland; America; Carbon-carbon ligases; Human; Linkage; Prevalence; Enzyme; Pathogenesis; Propionic acid; Metabolic diseases; Chromosome A3; Founder effect; Linkage equilibrium; Genetic determinism; Enzymopathy; Propionyl-CoA carboxylase; Genetic disease; Acidemia; Gene frequency; Gene; Ligases; Mutation; Carrier; Aminoacid disorder
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1086/302971

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, α and β, 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 β-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 β-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.