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.
Highlights
An increase in the concentration of phenylalanine (Phe) above the physiological norm is called hyperphenylalaninemia (HPA)
The DNA study of healthy Karachay-Cherkessia residents for the presence of frequent PAH pathogenic variants showed that the high incidence of HPA is caused by a significant frequency of PAH gene variants among Karachays
While Karachays constitute only 41% of the population of Karachay-Cherkessia, the wide distribution of PKU in this ethnic group accounts for the high incidence of PKU in the republic as a whole
Summary
An increase in the concentration of phenylalanine (Phe) above the physiological norm is called hyperphenylalaninemia (HPA). The main type of HPA is phenylketonuria (PKU; OMIM #261600). Phenylketonuria is an autosomal recessive inherited error of metabolism resulting from a deficiency in phenylalanine hydroxylase (EC 1.14.16.1), an enzyme that catalyzes the hydroxylation of phenylalanine to tyrosine, the rate-limiting step in phenylalanine catabolism [1]. Phenylketonuria is the most widespread aminoacidopathy in the world. The disease incidence is about 1:10000 worldwide and about 1:7000 in Russia [2]. PKU is included in neonatal screening programs, which have been conducted in Russia since 1991.
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