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

Propionyl CoA carboxylase (PCC) is a mitochondrial, biotin-dependent enzyme involved in the catabolism of amino acids, odd-chain fatty acids, and othe r metabolites. PCC consists of two subunits, alpha and beta, encoded by the PCCA and PCCB genes, respectively. Inherited PCC deficiency due to mutatio ns in either gene results in propionic acidemia (PA), an autosomal recessiv e disease. Surprisingly, PA is highly prevalent among Inuits in Greenland. We have analyzed reverse transcriptase-PCR products of the beta-subunit mRN A, to characterize the responsible mutation(s). A 3-bp insertion, 1540insCC C, was found in homozygous form in three patients and in compound heterozyg ous 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 popu lation, 310 anonymous DNA samples of Inuit origin were screened for 1540ins CCC. We found a carrier frequency of 5%, which is very high compared with t hose of most other autosomal recessive diseases. Analysis of alleles of a v ery closely linked marker, D3S2453, revealed a high degree of linkage diseq uilibrium between one specific allele and 1540insCCC, suggesting that this mutation may be a founder mutation.