Molecular-genetic causes for the high frequency of phenylketonuria in the population from the North Caucasus

PLoS One. 2018 Aug 1;13(8):e0201489. doi: 10.1371/journal.pone.0201489. eCollection 2018.

Abstract

Phenylketonuria is an inherited disease caused by mutations in the phenylalanine hydroxylase gene PAH. Different PAH pathogenic variants occur in different ethnic groups with various frequencies and the incidence of the disease itself varies from country to country. In the Caucasus region of Russia, some ethnoses are geographically and culturally isolated from each other. The tradition of monoethnic marriages may cause decreased genetic variability in those populations. In the Karachay-Cherkess Republic (Russia), the highest incidence of phenylketonuria in the world has been detected (1:850 newborns) in the region and 1:332 among the titular nation Karachays. Here, we showed that this phenomenon is due to the widespread prevalence of the p.Arg261* variant. Its allele frequency among Karachay patients with PKU was 68.4% and the carrier frequency in Karachays was 1:16 healthy individuals. PAH haplotype analysis showed a unique common origin. The founder haplotype and mutation "age" were estimated by analyzing the linkage disequilibrium between p.Arg261* and extragenic short tandem repeat loci. The p.Arg261* variant occurred in the Karachays population 10.2 ± 2.7 generations ago (275 ± 73 years) and its spread occurred in parallel with the growth of the population.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Gene Frequency
  • Haplotypes
  • Humans
  • Infant, Newborn
  • Linkage Disequilibrium
  • Pedigree
  • Phenylalanine Hydroxylase / genetics*
  • Phenylketonurias / epidemiology
  • Phenylketonurias / genetics*
  • Point Mutation*
  • Polymorphism, Genetic
  • Russia / epidemiology

Substances

  • Phenylalanine Hydroxylase

Grants and funding

The research was partially funded with the grant of Russian Foundation for Basic Research 18-015-00090 (prof. Rena A. Zinchenko), http://www.rtbr.ru/rffi/eng. The research was partially funded with the internal sources of the FSBI "Research Centre for Medical Genetics" as a part of its scientific program. The research was conducted as a part of the state assignment. There was no additional external funding received for this study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.