[Clinical and molecular genetic features of 3 family cases of the central precocious puberty, due to MKRN3 gene defects].

Gonadotropin-dependent precocious puberty (central) is a condition resulting from the early (up to 8 years in girls and 9 years in boys) reactivation of the hypothalamic-pituitary-gonadal axis. An increase in the secretion of sex steroids by the gonads in this form is a consequence of the stimulation of the sex glands by gonadotropic hormones of the pituitary gland. In the absence of central nervous system abnormalities, CPP is classified as idiopathic and as familial in some cases, emphasizing the genetic origin of this disorder. Loss-of-function mutations in Makorin Ring Finger Protein 3 (MKRN3) are the most common identified genetic cause of central precocious puberty compared to sporadic cases. In the present study we performed the first descrition of 3 family cases of central precocious puberty duo to novel MKRN3 gene mutation detected by NGS in the Russian Federation.

[Clinical and molecular genetic features of cases of isolated hypogonadotropic hypogonadism, associated with defects in GNRHR genes].

Congenital hypogonadotropic hypogonadism (CHH) is a rare disorder characterised by lack of pubertal development and infertility, due to deficient production, secretion or action of gonadotropin-releasing hormone (GnRH). Clinically, there are variants of CHH with hypo-/anosmia (Kalman syndrome) and normosmic hypogonadotropic hypogonadism. Given a  growing list of gene mutations accounting for CHH, the application of next generation sequencing (NGS) comprises an excellent molecular diagnostic approach because it enables the simultaneous evaluation of many genes. Biallelic mutations in GNRHR gene lead to the development of hypogonadotropic hypogonadism with normosmia. In this paper, we describe 16 patients with proven GnRH resistance and estimate the frequency of pathogenic variants in the GNRHR gene in the Russian population.

[Diagnostic algorithm for autosomal recessive ataxia]. / Algoritm diagnostiki autosomno-retsessivnykh ataksii.

AIM: To develop a complex algorithm for autosomal recessive ataxia (ARA) diagnosis applicable for Russian patients with degenerative ataxias. MATERIAL AND METHODS: 48 patients with of presumably degenerative ataxias were examined. Clinical evaluation was performed with the use of the SARA and ICARS scales (for ataxia) and MoCA (cognitive functions), and a set of laboratory tests was carried out, including electromyography, brain MRI, and DNA analysis of mutations responsible for Friedreich's disease and spinocerebellar ataxias (SCAs) types 1, 2, 3, 6 and 17. 28 patients underwent mutation screening using a multigenic MPS panel. RESULTS: 8 patients (16.7%) with non-hereditary causes of ataxia were identified: cerebellar alcoholic degeneration (n = 6) and multiple system atrophy of cerebellar type (n = 2); 3 patients (6.3%) with genetic ataxias were identified using routine DNA tests, such as with SCA type 1, 2 and 17, and 9 (18.8%) patients with Friedreich's disease. The MPS panel enabled molecular diagnosis of ARA in 8 patients (28.6%): ataxia-telangiectasia (n = 2), SANDO syndrome (n = 2), ataxia with oculomotor apraxia type 2 (n = 1), SCAR10 (n = 1), SCAR16 (n = 1), and atypical form of neuroaxonal dystrophy (n = 1). The diagnosis was not established in 20 patients. CONCLUSION: We have proposed an appropriate algorithm for degenerative ataxia diagnosis which is recommended to be used when examining patients with sporadic and autosomal recessive cases of the disorders with dyscoordination of movements.

[Contemporary pharmacogenetic approaches to the treatment of age-related macular degeneration].

A study on the role of CFH, HTRA and IL-8 gene polymorphism in age-related macular degeneration (AMD) development has been conducted. At the first stage of the study genetic testing was done in 69 patients with exudative AMD and 370 random Moscow citizens without the disease. The goal of the second stage was to determine the influence of gene polymorphism on patient's response to endovitreal ranibizumab treatment. For that, visual acuity and foveal thickness were assessed before and after ranibizumab injections in 120 patients with wet AMD. All patients were genotyped for the genes of interest. The results showed that the presence of homozygous 402H polymorphism in CFH gene, as well as homozygous (-625)A mutation in HTRA1 gene, determines certain clinical presentations. Moreover, visual acuity below 0.1 and presence of 402H, (-625)A and (-251)A alleles in both copies of all three genes (CFH, HTRA and IL-8) are negative predictors of disease severity and antiangiogenic treatment response.

[Influence of genetic mutations on clinical presentation of subretinal neovascularization. Report 2: The impact of HTRA and VEGF genes polymorphism].

A detailed analysis of influence of HTRA (serine peptidase) and VEGF (vascular endothelial growth factor) genes mutations is presented. The presence of one gene copy with allele of A- polymorphism rs1120638 of HTRA1 gen, T- polymorphism rs10490924 and de11443in54 of ARMS2 gene increases the risk of CNV in patients with AMD. The feature of clinical presentation in patients with CNV associated with (-625) A mutation of promoter region of HTRA1 gene in two chromosomes was fulminant course of the disease from exudative to scarring processes with fibrous tissue formation not just with sub-, but also intra- and preretinal localization. Genetic screening showed that combination of studied mutations (402H, (-625) A and (-251) A in both gene copies of CFH, HTRA and IL-8) results in the most severe and rapidly progressing form of the disease. Two new mutations were revealed in promoter region of VEGF gene: G > A replacement in position of (-72) nucleotide from transcription start and G > A replacement in 5'-nontranslated region of the 1st gene exon in position of (+31) nucleotide from transcription start.

[Influence of genetic mutations on clinical presentation of subretinal neovascularization. Report 1: The impact of CFH and IL-8 genes polymorphism].

Genetic analysis was performed in patients with subretinal neovascularization (CNV). The results showed significant association of CFH (compliment factor H) gene polymorphism with increase (rs1061170, rs514943 and rs380390) or decrease (rs529825, rs7524776, rs1831281, rs2274700, rs1576340, rs12144939, rs7540032) of CNV development risk. The incidence of IL-8 gene mutation was significantly (p = 0.008) higher in patients after chorioretinitis. Apparently -125 > A polymorphism in patients with chorioretinitis increases risk of CNV development, thus promoting raise of proangiogenic factors concentration in eyes with inflammatory background. The clinical presentation in patients with AMD and myopic disease associated with (-125) A mutation of promoter region of IL-8 gene was similar to that of patients with chorioretinitis. The features are the following: focal pattern, no drusen and RPE detachment, predominantly classic form of CNV (without occult pattern), formation of well-organized newly developed vessels.

[Contribution of rennin-angiotensin-aldosterone system genes and NO synthase gene to the development of arterial hypertension].

Arterial hypertension (AH) is one of the most widespread cardiovascular disorders, 39.2% of men and 41.1% of women having elevated arterial pressure (AP). Hence, the necessity to elucidate possible causes of this abnormality. Heredity is considered to be a major factor determining AP in humans, and researchers all over the world are engaged in the search for AP markers. This paper is focused on genes controlling the renin-angiotensin-aldosterone system, viz. genes of angiotensin II, type 1 angiotensin II receptors, angiotensin-converting enzyme, and NO synthase. An overview of population studies with special reference to these genes indicates that molecular-genetic mechanisms of AH remain unclear. Joint efforts of researchers working in different centres are needed to address the problem.

Association of haplotypes of interleukin-10 gene with the risk of cancer.

Polymorphisms of promotor region of IL-8, IL-10, and IL-12 genes were analyzed in cancer patients and subjects without history of cancer. The distribution of alleles of the analyzed polymorphisms in the control group coincided with that in other Caucasian populations. The incidences of three IL-10 gene polymorphisms (G-1082A, C-819T, and C-592A) significantly differed in controls and patients. Of 8 theoretically probable IL-10 gene haplotypes determined by these polymorphisms, 3 variants were revealed. Haplotype ACC was more incident in cancer patients, while ATA haplotype was rarer. The results are in line with the findings of other studies indicating the involvement of the immune system genes in the pathogenesis of cancer.

[Allele Frequency Analysis of Four Single Nucleotide Polymorphisms Locating in Promoter and 5'-Untranslated Regions of ABCAI Gene in Young Men - Survivors From Myocardial Infarction]. / Analiz chastoty vyiavleniia chetyrekh strukturnykh polimorfizmov DNK v promotornoi i 5'-netransliruemykh oblastiakh gena ABCA1 u muzhchin, perenesshikh infarkt miokarda v molodom vozraste.

Analysis of allele distribution of four single nucleotide polymorphisms (C-17G, C69T, G-191C and 319insG) of promoter and 5'-untranslated regions of the ABCA1 gene was carried out in a sample of 171 men, who had survived myocardial infarction before 45 years, and in controls. Two-fold increase of T69 and C-191 allele frequencies were observed in Russian population in comparison to Dutch one. While comparing allele and genotype distributions of the polymorphisms in the samples under study no statistically significant differences were found, so as no influence of different alleles on lipid spectrum data was observed. Role of polymorphisms under study appears to be insignificant in formation of genetic susceptibility to myocardial infarction in young men.

Apolipoprotein B 3'-VNTR polymorphism in Eastern European populations.

Apolipoprotein B 3' (3' ApoB) minisatellite polymorphism was studied in healthy unrelated individuals from the Russian Federation and the Republic of Belarus, in 10 populations from five ethnic groups: Russians, Byelorussians, Adygeis, Kalmyks and Yakuts. The analysis was carried out using PCR and electrophoresis followed by silver staining. Overall, 25 alleles of the 3' ApoB minisatellite, ranging from 25 to 55 repeats, were detected. Heterozygosity indices were high and varied from 0.73 to 0.84. The distributions of alleles of this minisatellite in the Caucasoid populations (Russians, Byelorussians and Adygeis) had a bimodal character, whereas that for Mongoloid populations (Kalmyks and Yakuts) had a unimodal distribution. Nei's genetic distances between the populations studied and some reference populations of Europe and Asia were estimated. Despite their allele distribution homogeneity, different East Slavonic ethnic groups were clearly resolved by multidimensional analyses. The East Slavonic and Adygei populations revealed a high similarity with European Caucasoids. The Mongoloid populations (Kalmyks and Yakuts) were considerably different from those of the European Caucasoid populations, but were similar to other Asian Mongoloid populations. The results demonstrate the variability of 3' ApoB minisatellite polymorphism not only in distant populations but also, to a certain extent, in genetically relative ones.

[Dystrophin gene expression in patients with Duchenne muscular dystrophy after myoblast transplantation]. / Ekspressiia gena distrofina u bol'nykh miodistrofiei Diushenna posle transplantatsii mioblastov.

Based on originally designed technique of myoblast cultivation and in accordance with the approved by the Russian Ministry of Health "one muscle treatment" protocol of myoblast transplantation to the Duchenne muscular dystrophy patients, the first in Russia clinical trial of this gene correction method was carried out. Immonologically related myoblast cultures (30 to 90 million cells per patient) were injected after all preliminary procedures into tibialis anterior muscles of four boys selected from a group of volunteer recipients (Duchenne muscular dystrophy patients) based on the analysis of a number of surface antigens in donor-recipient pairs. The condition of the patients remained satisfactory during the whole period of post-transplantation follow-up (from 6 months to 1.5 years). Six months after myoblast transplantation the presence of donor DNA or dystrophin synthesis was demonstrated in muscle biopsies of three out of four patients. This result confirms efficacy and safety of the procedure used.

Apolipoprotein B 3'-VNTR polymorphism in the Udmurt population.

An analysis of a highly polymorphic region of the apolipoprotein B gene 3'-end DNA (Apo B 3'-VNTR), represented by 10 alleles, was carried out using the polymerase chain reaction. Data inferred from the principal component analysis indicate that the Udmurts occupy an isolated position among the populations constituting the northern branch of Caucasoid peoples.

High incidence of 550delA mutation of CAPN3 in LGMD2 patients from Russia.

Autosomal recessive limb gird muscular dystrophy (LGMD2) is a clinically and genetically heterogeneous group of diseases that are characterized by progressive atrophy and weakness of the proximal limb muscles. At least eight genetic loci leading to LGMD2 are recognized. The proportion of particular gene involved in producing different forms of LGMD2 shows a marked geographical variation. We studied 19 LGMD2 patients from Russia (15 families) and found calpain 3 (CAPN3) gene mutations in most of the patients studied. Sequence analysis of the fourth exons revealed two sibs - heterozygous compound for a 15-bp deletion (nt598-612) and 550 adenine deletion, and two sibs homozygous for a 550delA. We developed assay based on allele specific amplification (ASA) for rapid screening of the 550delA. The ASA assay of the LGMD2 patients under study showed that 7 patients from 6 families were homozygous for 550delA and 7 patients from 4 families were heterozygous for 550delA. A linkage analysis employing four microsatellites flanking the LGMD2A locus was performed. We found complete haplotype identity in most cases what favors the possibility of a common founder. Heterozygous carriers of 550delA were found in general population. The crude estimate of the mutation frequency is 1/150. Hum Mutat 15:295, 2000.

[Highly polymorphic regions of the genes for apolipoprotein B and angiotensin-converting enzyme in the Udmurt population]. / Izuchenie vysokopolimorfnykh uchastkov genov apolipoproteina B i angiotenzin-konvertiruiushchego germenta v populiatsii Udmurtov.

The hypervariable regions of the 3'-end of the apolipoprotein B gene (APOB3'-VNTR) and angiotensin converting enzyme gene (ACE), which had 10-15 alleles each, were studied in a sample from the Udmurt population by means of polymerase chain reaction (PCR). From the literature data, the genetic position of Udmurts among 12 groups of Caucasoid, Mongoloid, and Negroid populations was determined. The data obtained by the method of principal components indicated that Udmurts held an isolated position in the northern branch of the Caucasoid race.

[Allelic variants of apolipoproteins B and CII genes in patients with ischemic heart disease and in healthy persons from the Moscow population]. / Allel'nye varianty genov apolipoproteinov B i SP u bol'nykh ishemicheskoi bolezn'iu serdtsa i u zdorovykh lits iz Moskovskoi populiatsii.

Allelic frequencies of a microsatellite of the apolipoprotein CII gene (APOCII) and a minisatellite of the apolipoprotein B gene (APOB) were studied using polymerase chain reaction (PCR). The study was conducted on a random sample of male Moscow inhabitants and a sample of patients with coronary heart disease (CHD) from the same population. Fourteen variants of the APOB minisatellite (the 82% heterozygosity level) and 13 alleles of the APOCII microsatellite (the 85% heterozygosity level) were found. CHD patients significantly differed from the control group in the distributions of alleles in these loci: APOB 32, APOB 46, APOB 48, and APOB 50 as well as APOCII 17 and APOCII 29 were found more frequently. A relationship was found between the distributions of APOB and APOCII in the CHD patients. The CHD patients with alleles APOCII 21 and APOCII 30 very often had the allele APOB 32; and patients with the genotype APOB 34, 36 had the allele APOCII 29 even more often than affected individuals in general. Individuals of the control group with the allele APOCII 30 exhibited hypertriglyceridemia without increased levels of total cholesterol and apolipoprotein B in plasma.

[Analysis of allelic variants of the hypervariable locus of apolipoprotein B in Bashkir and Komi populations]. / Analiz allel'nykh variantov gipervariabel'nogo lokusa apolipoproteina B v populiatsiiakh Bashkir i Komi.

Allelic variation of the hypervariable apolipoprotein B gene locus (ApoB) in three groups of the Bashkir population and in the Komi population was analyzed. Among 219 individuals studied, 13 allelic variants were identified with the number of repeats ranging from 28 to 52. The frequency of alleles varied from 0.01 to 0.51 with the mean heterozygosity index being 0.66 in the Bashkir population and 0.74 in the Komi one. Considerable difference in the frequency distribution of the ApoB loci genotypes between the Bashkir and Komi populations was observed, and the distribution patterns for Bashkirs from Abzelilovskii and Ilishevskii regions deviated from the Hardy-Weinberg equilibrium. The genetic distance between the Bashkir and Komi populations calculated on the basis of allele frequencies at the hypervariable ApoB gene locus corresponded to the expected degree similarity of the populations studied. Thus, this locus can be recommended as an informative marker for studying the gene pool and genetic processes in the populations because of the high level of its polymorphism and the heterozygosity in the populations.