Mutation spectrum of the PAH gene in phenylketonuria patients in the Karachay-Cherkess Republic (Russia)

Гундорова, П.; Степанова, Анна; Makaov, A. Kh.; Зинченко, Р. А.; Abaykhanova, Z. M.; Polyakov, A. V.

doi:10.1134/s1022795416110041

Cited by 8 publications

(6 citation statements)

References 15 publications

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“…Six PAH variants can be detected by this method: p.Arg413Pro, p.Arg408Trp, p.Phe331Ser, p.Arg261*, p.Pro211Thr, and p.Pro211Leu. The overall allele frequency (calculated among patients) is 76.8% for KCR residents in general and 81.4% for Karachays [ 9 ]. Carrier frequency and disease incidence were calculated, taking into account the effectiveness of the method.…”

Section: Resultsmentioning

confidence: 99%

“…All PAH gene variants in the paper are related to the reference sequence NM_000277.1. A custom allele-specific MLPA panel with polyacrylamide electrophoresis visualization was created earlier based on the PKU mutation spectrum in the KCR [ 9 ]. PAH variants p.Arg413Pro (c.1238G>C), p.Arg408Trp (c.1222C>T), p.Phe331Ser (c.992T>C), p.Arg261* (c.781C>T), p.Pro211Thr (c.631C>A), and p.Pro211Leu (c.632C>T) were studied in healthy Karachay-Cherkessia residents.…”

Section: Methodsmentioning

confidence: 99%

“…Interestingly, the p.Arg261* (c.781C>T) PAH variant is very widespread among them. The allele frequency of p.Arg261* is 68.4% among PKU patients and 32.5% among mHPA patients [ 8 , 9 ], so it is the predominant variant in this region. The presence of those genetic peculiarities in Karachay-Cherkessia presumably results from reproductive isolation and genetic drift in populations residing on this territory.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2018

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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.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2018

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“…In three patients with HPA, only one allele is identified (3%). Identified 25 patients from KChR with HPA caused by PAH gene mutations (or at least one mutation) discussed in References [19,20]. According to newborn screening in the KChR, very high birth prevalence of HPA was determined, which is 1:850 newborns (PKU only-1:1581 newborns), 1:332 in Karachays, while the average prevalence at birth in Russia is 1:7000.…”

Section: Genetic Heterogeneity (Allelic Locus) Of Monogenic Hereditamentioning

confidence: 99%

“…Polyakov). Variety of methods were used for DNA diagnosis-Sanger sequencing, MLPA, RFLP, AFLP, whole exome sequencing-Depending on the studied nosology according to the protocols published elsewhere by the authors of current manuscript [19][20][21][22][23].…”

Section: Molecular Genetic Analysismentioning

confidence: 99%

Epidemiology of Hereditary Diseases in the Karachay-Cherkess Republic

Зинченко

Makaov²,

Marakhonov

et al. 2020

IJMS

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Prevalence and allelic heterogeneity of hereditary diseases (HDs) could vary significantly in different human populations. Current knowledge of HDs distribution in populations is generally limited to either European data or analyses of isolated populations which were performed several decades ago. Thus, an acknowledgement of the HDs prevalence in different modern open populations is important. The study presents the results of a genetic epidemiological study of hereditary diseases (HDs) in the population of the Karachay-Cherkess Republic (KChR). Clinical screening of a population of 410,367 people for the identification of HDs was conducted. The population surveyed is represented by five major ethnic groups—Karachays, Russians, Circassians, Abazins, Nogais. The study of the populations was carried out in accordance with the proprietary protocol of genetic epidemiological examination designed to identify >3500 HDs easily diagnosed during clinical examination by qualified specialists specializing in the HDs. The protocol consists of the population genetic and medical genetic sections and is intended for comprehensive population analysis based on the data on different genetic systems, including the genes of HDs, DNA polymorphisms, demographic data collected during hospital-based survey. 8950 families (with 10,125 patients) with presumably the HDs were initially identified as a result of the survey and data collection through various sources of registration (from 1156 medical workers from 163 medical institutions). A diagnosis of hereditary pathology was established in 1849 patients (from 1295 families). Two hundred and thirty nosological forms were revealed (in 1857 patients from 1295 families). The total prevalence of HDs was 1:221. Differences between populations and ethnic groups were identified: 1:350 in Russians, 1:195 in Karachays, 1:199 in Circassians, 1:218 in Abazins, 1:135 in Nogais. Frequent diseases were determined, the presence of marked genetic heterogeneity was identified during the confirmatory DNA diagnosis. To explain the reasons for the differentiation of populations by load of HD, a correlation analysis was carried out between the FST (random inbreeding) in populations and HDs load values. This analysis showed genetic drift is probably one of the leading factors determining the differentiation of KChR populations by HDs load. For the first time, the size of the load and spectrum of HDs in the populations of the KChR are determined. We have demonstrated genetic drift to be one of the main factors of the population dynamics in studied population. A significant genetic heterogeneity of HDs, both allelic and locus, was revealed in KChR.

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Genotyping of patients with phenylketonuria from different regions of Russia for determining BH4 responsiveness

et al. 2017

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Mutation spectrum of the PAH gene in phenylketonuria patients in the Karachay-Cherkess Republic (Russia)

Cited by 8 publications

References 15 publications

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

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

Epidemiology of Hereditary Diseases in the Karachay-Cherkess Republic

Genotyping of patients with phenylketonuria from different regions of Russia for determining BH4 responsiveness

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