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

<div><p>Phenylketonuria is an inherited disease caused by mutations in the phenylalanine hydroxylase gene <i>PAH</i>. Different <i>PAH</i> 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. <i>PAH</i> 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.</p></div

Linkage disequilibrium analysis between the p.Arg261* variant in Karachays and microsatellites close to the <i>PAH</i> gene.

<p>Linkage disequilibrium analysis between the p.Arg261* variant in Karachays and microsatellites close to the <i>PAH</i> gene.</p

Karachay population dynamics from 1790 to 2010.

<p>The dots indicate the population numbers of the Karachay population [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0201489#pone.0201489.ref027" target="_blank">27</a>]. The curve is the approximation of exponential dependence on the graph of abundance versus time. The point of p.Arg261* origin is marked by an arrow; the error interval is in a square.</p

Survey data of healthy KCR residents.

<p>Survey data of healthy KCR residents.</p

Haplotypes of p.Arg261*-bearing chromosomes at five microsatellite loci.

<p>Haplotypes of p.Arg261*-bearing chromosomes at five microsatellite loci.</p

Genetic analysis of autosomal recessive osteopetrosis in Chuvashiya: the unique splice site mutation in TCIRG1 gene spread by the founder effect

The rare malignant disorder autosomal recessive osteopetrosis (OPTB) is one of the most prevalent autosomal recessive diseases in the Chuvash Republic of Russia. The purpose of this study was to determine the underlying molecular cause of osteopetrosis in Chuvashiya and to reveal the factors causing the unusual high frequency of the disease in this region. Having assumed a founder effect, we performed linkage disequilibrium (LD) mapping of the OPTB locus at the TCIRG1 region and found a unique splice site mutation c.807+5G>A in all Chuvashian OPTB patients studied. We then analyzed the mutational change in mRNA and detected an intron insertion within the mutant transcript, resulting in a frameshift and premature stop-codon formation (p.Leu271AspfsX231). A decreased expression of the mutant transcript was also detected, which may have been the result of nonsense-mediated decay. Real-time qPCR and MLPA® melting curve analysis-based systems were designed and used for c.807+5G>A mutation screening. In addition to analyzing the gene frequency in Chuvashiya, we also estimated three other populations in the Volga-Ural region (Mari, Udmurt and Bashkir). We found a 1.68% prevalence in Chuvashiya (calculated disease frequency, 1/3500 newborns) and a 0.84% in the Mari population (1/14 000 newborns). The haplotype analysis revealed that all OPTB cases in Chuvashians and Marians originated from a single mutational event and the age of the mutation in Chuvashians was estimated to be approximately 890 years