[MFN2 gene analysis in patients with hereditary motor and sensory neuropathy from Bashkortostan Republic].

Hereditary motor and sensory neuropathy (HMSN) type IIA is caused by mutations in the mitofusin type-2 (MFN2) gene and represents one of the most common axonal forms of HMSN. We determined the spectrum and frequency of MFN2 gene mutations in patients from the Bashkortostan Republic (BR). Four different mutations were revealed in 5 out of 170 unrelated patients, i.e., c.2113G>A (p.Val705Ile) (1.2% among all types of H MSN in the total sample of patients and 2% among patients of Tatar ethnicity). This mutation was described previously; c.775C>T (p.Arg259Cys) (0.6%, in the total sample of patients and 2% among the patients of Tatar ethnicity); c.776G>A (p.Arg259His) (0.6% in the total sample of patients and 1.5% among the patients of Russians ethnicity); and c.2171T>C (p.Leu724Pro) (1.2% in the total sample of patients and 7.4% among the patients of Bashkirs ethnicity). These are new mutations that were not observed among healthy family members and in control samples of healthy subjects. Five identified nucleotide substitutions represent single nucleotide polymorphisms of the gene, including c.892G>A (p.Gly298Arg), c.957C>T (Gly319Gly), and c1039-222t>c, which were described previously, while c.175+28c>t and c.2204+15t>c represent new nucleotide substitutions in the intron regions of the gene.

[Genetic epidemiological study of monogenic hereditary diseases in the Republic of Tatarstan: population dynamic factors determining the differentiation of the load of hereditary diseases in five districts].

A genetic epidemiological study has been performed in five districts of the Republic of Tatarstan, Russia: Arsky, Atninsky, Kukmorsky, Buinsky and Drozhzhanovsky raions. The total size of the population surveyed is 188 397 people. Tatars accounted for 77.13% of the population analyzed (145466 people) and were represented by two main ethnic groups: Kazan Tatars and Mishars. The medical genetic study encompassed the total population of the districts, irrespective of ethnicity, and was carried out according to the standard protocol developed in the Laboratory of Genetic Epidemiology of the Research Center for Medical Genetics of the Russian Academy of Medical Sciences. After segregation analysis, the prevalence rates of the main types of monogenic hereditary disorders (MHDs), i.e., autosomal dominant (AD), autosomal recessive (AR), and X-linked diseases, have been calculated for the total population of the five districts and for Tatars alone. The prevalence rates ofAD, AR, and X-linked diseases considerably vary in different subpopulations. The largest difference in the MHD prevalence rate has been found between the rural and urban populations. The overall prevalence rate of MHDs was one patient per 293 urban residents and populations and one patient per 134 rural residents, with a wide variation between subpopulations, from 1 : 83 people in the rural population of Atninsky raion to 1: 351 people in the town of Kukmor. Comparison of the MHD prevalence rate in Tatars with those in populations surveyed earlier has shown that the characteristics of the load of MHDs in the Tatar population are similar to those in some districts of the republics of Bashkortostan, Udmurtia, Mari El, and Chuvachia. In Russian populations of European Russia, the MHD prevalence rates are substantially lower. Correlation analysis has shown high (r = 0.5-0.9) significant correlations between the local inbreeding (a), the im index, the random inbreeding (F(ST)), and the AD and AR prevalence rates in the Tatar population. This analysis has demonstrated that genetic drift is the main population dynamic factor determining the MHD load in the Tatar population.

Association of cytokine gene alleles with the inflammation of human periodontal tissue.

Gingivitis and periodontitis are chronic inflammatory diseases of the periodontal tissue in humans caused by both environmental and genetic factors. The human cytokine genes that regulate the immune response may play an important role in the development of these chronic inflammatory diseases. The aim of this study is to analyze the allele status of eight human cytokine genes and to associate it with the inflammation of periodontal tissue in humans. A total of 296 unrelated males of Russian origin were studied. A significant association of theIL1BandIL6 minor alleles and gingivitis was found. In addition, we found a significant association of the OHI-S index with theIL18gene alleles. The influence of genetic factors on gingivitis may contribute to the understanding of the mechanisms of interaction between genetic and environmental factors in periodontal conditions, and to the identification of risk groups for effective prevention and treatment.

A new variant of Charcot-Marie-Tooth disease type 2 is probably the result of a mutation in the neurofilament-light gene.

Charcot-Marie-Tooth (CMT) disease is the most common inherited motor and sensory neuropathy. The axonal form of the disease is designated as "CMT type 2" (CMT2). Although four loci known to be implicated in autosomal dominant CMT2 have been mapped thus far (on 1p35-p36, 3q13. 1, 3q13-q22, and 7p14), no one causative gene is yet known. A large Russian family with CMT2 was found in the Mordovian Republic (Russia). Affected members had the typical CMT2 phenotype. Additionally, several patients suffered from hyperkeratosis, although the association, if any, between the two disorders is not clear. Linkage with the CMT loci already known (CMT1A, CMT1B, CMT2A, CMT2B, CMT2D, and a number of other CMT-related loci) was excluded. Genomewide screening pinpointed the disease locus in this family to chromosome 8p21, within a 16-cM interval between markers D8S136 and D8S1769. A maximum two-point LOD score of 5.93 was yielded by a microsatellite from the 5' region of the neurofilament-light gene (NF-L). Neurofilament proteins play an important role in axonal structure and are implicated in several neuronal disorders. Screening of affected family members for mutations in the NF-L gene and in the tightly linked neurofilament-medium gene (NF-M) revealed the only DNA alteration linked with the disease: a A998C transversion in the first exon of NF-L, which converts a conserved Gln333 amino acid to proline. This alteration was not found in 180 normal chromosomes. Twenty unrelated CMT2 patients, as well as 26 others with an undetermined form of CMT, also were screened for mutations in NF-L, but no additional mutations were found. It is suggested that Gln333Pro represents a rare disease-causing mutation, which results in the CMT2 phenotype.

[Hereditary nervous system diseases in Mordovia]. / Nasledstvennye bolezni nervnoi sistemy v Mordovii.

A medical genetic study on hereditary neural diseases was performed in 21 districts of the Mordovian Republic. The total number of persons examined was 936,800. The population load of autosomal dominant, autosomal recessive, and X-linked recessive diseases was 0.1696 +/- 0.0129, 0.1075 +/- 0.0107, and 0.0341 +/- 0.0010, respectively. Twenty-eight disease entities were revealed, including 10 autosomal recessive (AR), 15 autosomal dominant (AD), 2 X-linked recessive (XR) diseases, and 1 genetically heterogenous disease. These diseases were nonuniformly distributed among different populations of Mordovia. The incidence of AR diseases was highest in the Mordovian and Tatar populations; that of AD diseases, in the Russian population; and that of XR diseases, in the Mordovian population.

[Genetic structure and the load of hereditary diseases in five populations of Arkhangel'skaia region]. / Geneticheskaia struktura i gruz nasledstvennykh boleznei v piati populiatsiiakh Arkhangel'skoi oblasti.

A population and medical genetic investigation was performed in a number of raions in the Arkhangel' skaya oblast. Random inbreeding coefficients were 0.000358 and 0.000361 in the Vinogradovskii and Krasnoborskii raions. Malecot's local inbreeding coefficients were 0.000565 and 0.000472, respectively. The endogamy indices were 0.37 and 0.54, respectively. In the urban population, the loads of autosomal dominant, autosomal recessive, and X-linked pathology were 1.01 and 0.98 per 1000 individuals, and 0.29 per 1000 men; in the rural population, they were 1.22, 1.55, and 1.08, respectively. In the populations studied, the hereditary pathology spectrum is described.

Linkage of polymorphic congenital cataract to the gamma-crystallin gene locus on human chromosome 2q33-35.

Cataract is one of the major causes of blindness in humans. We describe here an autosomal dominant polymorphic congenital cataract (PCC) which is characterised by wide variations in phenotype of non-nuclear lens opacities, even among affected members of the same family. PCC families included a large, unique pedigree (254 members, 103 affected individuals), and genetic linkage was conducted using a variety of polymorphic markers. Evidence for linkage was found for chromosome 2q33-35 with PCC mapping near D2S72 and TNP1. A tri-nucleotide microsatellite marker for gamma-crystallin B gene (CRYG1) was found to co-segregate with PCC and yielded a maximum lod score of 10.62 at (theta = 0). A multipoint analysis demonstrated that the most probable location of the PCC gene was within an 8 cM genetic interval containing the gamma-crystallin gene cluster. These data provide strong evidence of the existence of an autosomal dominant mutation for PCC in or near the gamma-crystallin gene cluster. This defect is characterised by complete penetrance but variable expression of the cataract phenotype. Our study also suggests that non-nuclear human cataracts might be caused by some abnormality in gamma-crystallin genes.

[Genetic study of idiopathic torsion dystonia in Russia]. / Geneticheskoe izuchenie idiopaticheskoi torzionnoi distonii v Rossii.

Inheritance of idiopathic torsion dystonia (ITD) was studied in 41 Russian families including 41 probands with generalized, focal, and segmental dystonia and 140 recurred cases. Affected relatives appeared in two or more generations in 31 families analyzed. It was shown that in 76% of segregated cases, ITD was inherited as an autosomal dominant trait with a penetrance of 40% and varying expression. An autosomal recessive type was observed in 24% of the cases. Approximately 10% of the cases of disease could be caused by a new mutation and 14.6% by a nongenetic phenotype similar to genetic forms in its clinical symptoms. ITD with the X-linked recessive type of inheritance did not occur in the families studied. The recurrence risk was 20% in autosomal dominant forms. The risk correlated with age the relative's: clinical symptoms developed in 98.4% of patients by the age of 30.

[Population genetics of spinal muscular atrophy]. / Populiatsionnaia genetika spinal'nykh myshechnykh atrofii.

A population genetic study of spinal amyotrophy (SMA) in six Russian and three Central Asian regions was carried out. In total, 29 patients with autosomal recessive (AR) infantile proximal SMA (SMA I-III) and four patients with rare SMA forms with an unspecified type of inheritance were revealed. In Russian populations, the prevalence of SMA I-III is similar (1.5-2.5/100000), it is one of the most common hereditary neurological diseases. A tendency toward nonuniform territorial SMA prevalence is observed in genetically subdivided populations. The lesser SMA I-III prevalence in Central Asian populations might be due in part to inbreeding depression. A segregation frequency of 0.21 is in accordance with AR inheritance; the proportion of sporadic cases is 3%. Clinical genealogical data support the genetic unity of forms I-III. The origin of pedigrees with SMA in distant relatives is discussed.

[Hereditary spastic paraplegias: a comparative study of Russian populations]. / Nasledstvennye spasticheskie paraplegii: svranitel'noe issledovanie rossiiskikh populiatsii.

15 families (27 patients) with hereditary spastic paraplegia (HSP) were found in the course of monogenic disorders investigation in 6 Russian populations. High HSP prevalence (7.21+1.61) x 10(-5) was found in Kirov Province [the frequency of the gene of autosomal-dominant form was (3.61 +/- 1.14) x 10(-5), autosomal-recessive-(64.5 +/- 9.74)- 10(-6)]. The pronounced interfamilial polymorphism of HSP was observed. Two families with rare autosomal-recessive variation of "clear" HSP as well as two families with HSP associated with peroneal amyotrophies were revealed. Accumulation of cases with unusual combination of autosomal-dominant HSP together with mental deficiency was remarkable in Kirov Province.

Emery-Dreifuss syndrome: genetic and clinical varieties.

Two familial and 2 sporadic cases of Emery-Dreifuss syndrome are reported. One family presented a rare autosomal dominant variant of Emery-Dreifuss muscular dystrophy, another with X-linked recessive inheritance showed unusual intrafamilial variability. One of sporadic cases closely resembled rigid spine syndrome, the other was clinically intermediate between Emery-Dreifuss muscular dystrophy and rigid spine syndrome, showing that they are not distinct disorders.

[Population genetic study of hereditary motor and sensory neuropathy in the Kirov region]. / Populiatsionno-geneticheskoe issledovanie nasledstvennoi motorno-sensornoi nevropatii v kirovskoi oblasti.

All the cases of hereditary motor and sensory neuropathy (HMSN) in an eastern part of Kirov region (Russian north-east) were ascertained (N = 42 including 11 persons with pre/subclinical forms; m: f = 1). HMSN prevalence is 15.95 +/- 2.47.10(-5) being higher in rural than in urban populations. The distribution of HMSN families (total 16) in 9 districts of the region is uneven. HMSN is the most common of all hereditary muscular disorders in the region. Autosomal dominant inheritance was established in 12 families, AD gene frequency is 10.90 +/- 2.90.10(-5) gene penetrance being 90%. Sporadic cases were few (N = 4; 9.76%). No proven autosomal recessive or X-linked inheritance was found out.

[Structure and variability of hereditary disease in the Kirov Province]. / Struktura i raznoobrazie nasledstvennoi patologii v Kirovskoi oblasti.

The main purpose of this report is to present the nosological spectrum of hereditary diseases in 9 Districts of Kirov Province and to compare it with that studies earlier in other Russian populations. This comparison is undertaken in an attempt to define a "nucleus" of hereditary diseases in the Russian population studied. During this study 343 families with 546 affected were registered. The spectrum covered 55 different autosomal dominant, 14 autosomal recessive and 11 X-linked recessive hereditary disorders in the population under study. Some of these forms could be considered as common forms for the whole Russian population, because they were met in all Russian populations which were analysed. This conclusion is proved by the cluster analysis of genetic distances calculated on the basis of gene frequencies for autosomal recessive hereditary disorders.

[Further analysis of location of the gene for inborn dominant Nochurli cataract]. / Dal'neishii analiz lokalizatsii gena dominantnoi vrozhdennoi nokhurskoi katarakty.

The study of location of the gene for inborn dominant nokhur kataracta is going on. No linkage of this gene with the locus of alpha-globin gene (16p13.3) and the locus (7q36-qter) was revealed. Additional evidence was obtained for a possible location of the gene for inborn dominant nokhur kataracta on the 14 chromosome. The maximal lod value equaled to 1.089 at theta = 0.20 in the analysis of kataracta genes and alpha-1-antitrypsin (14q32.1), and 0.846 at theta = 0.30 for the kataracta gene and D14S13 (14q32.1-q32.32). For the alpha-1-antitrypsin gene the maximal lod value was 2.24 at theta = 0.05.

[Prevalence of hereditary pathologies in residents of the Kirov Province]. / Otiagoshchennost' naseleniia kirovskoi oblasti nasledstvennoi patologiei.

Medical-genetic study was carried out in the population of Kirov Province (population size about 120.000). 203 families with 334 affected with hereditary disorders were registered. The correctness of pathology classification for the inheritance type was confirmed by segregational analysis. The load of hereditary diseases in the population was: 1.25 +/- 0.06 for autosomal dominant, 1.37 +/- 0.07 for autosomal recessive and 0.22 +/- 0.06 for X-linked recessive disorders. It is suggested that variability in the values of the load of autosomal recessive disorders is determined to the large extent by genetic structure of the population.

[An attempt to locate the gene for congenital cataracts using linkage analysis]. / Popytka lokalizatsii gena vrozhdennoi katarakty s pomoshch'iu analiza stsepleniia.

Analysis of linkage between the gene of autosomal dominant congenital cataract and 10 polymorphic loci localized in 1, 2, 3, 4, 6, 13, 16 chromosomes was performed. Some loci were only informative for this purpose: Mucin located in 1q21, NH24 located in the 2-nd chromosome and Pi located in 1q21 32.17. No linkage was observed for the cataract gene and the loci located in chromosomes 1 and 2. The maximum estimate of likelihood is approx. 0.2 for the cataract gene and the Pi locus located in 14q32.1, though the value of the maximal lod score was only, 0.732.

[Variety of hereditary diseases in the Adygei Autonomous Region]. / Raznoobrazie nasledstvennykh boleznei v Adygeniskoi Avtonomnoi oblasti.

This report is one of the series of communications dedicated to medico-genetical description of the Adyg population in the autonomous national district. The peculiarities have been considered of the forms of hereditary diseases both in the Adyg and Russian populations neighbouring each other in the Adyg national district territory. It was inferred that the minimal distance between Adyg and Russian populations consists in the level of aggregation and variety of autosomal-recessive forms which depended on subdivision and the level of inbreeding in the populations studied.

[Correction for the estimated load of hereditary diseases in the population of the Krasnodarsk district]. / Popravka k otsenke gruza nasledstvennykh boleznei v populiatsii krasnodarskogo kraia.

Medico-genetical examination of children from 6 invalid houses, 2 asylum houses, 3 internate schools and 1 house for deaf and feeble-hearing children as well as from the internate school for children with poor vision was undertaken in Krasnodar district. 10.6% of the children were found to have chromosomal abnormality, 26.5%--multifactorial pathology and 62.9% of children were affected by monogenic diseases. The spectrum of diseases covers 20 forms, 8 of them being autosomal-dominant, 10--autosomal-recessive and 2--X-linked forms. A "selective" method presented in this article for revealing patients affected by genetical diseases in specialised institutions permitted to evaluate a portion of the patients having been not identified when using the "survey" expeditional method of population--epidemiological study of the district population. This portion constitutes 19%. The more accurate values of genetic load in populations of Krasnodar district were obtained, being 1.06-0.06 for autosomal-dominant, 0.78-0.05 for autosomal-recessive and 0.38-0.05 for X-linked diseases per thousand.

[Load of hereditary diseases in the populations of the Adyg autonomic district]. / Gruz nasledstvennykh boleznei v populiatsiiakh adygeiskoi avtonomnoi oblasti.

Comparative analysis of the loads of hereditary diseases in two ethnically different populations coexisting in the Adyg national district was performed. The modes of inheritance of diseases studied were tested by segregational analysis. The results obtained demonstrated that the load of autosomal-recessive diseases in the populations of the Adyg national district is higher than that in Russian population, while the load of autosomal-dominant diseases is similar in two populations. This difference in the level of the loads appear to be connected with genetic structure of the populations studied. Regressional analysis of relations between loads and the level of inbreeding in the Adyg population showed the explicit interrelation between the load of autosomal-dominant diseases and the Fst correlation coefficient being 0.89.

[Spectrum and territorial distribution of hereditary diseases in the population of the Krasnodar Krai]. / Spektr i territorial'noe rasprostranenie nasledstvennykh boleznei v populiatsiiakh Krasnodarskogo Kraia.

The analysis of the spectrum of hereditary diseases in the population of the Krasnodar province is performed and the influence of the population dynamics factors on the spectrum is discussed. More than 130 nosological forms were discovered in the population of approx. 200,000. Among these, there are 63 autosomal dominant, 49 autosomal recessive and 17 X-linked recessive forms. Of the most frequent autosomal dominant diseases (more than 1 per 50,000) autosomal recessive and X-linked recessive disorders 13, 7 and 7 forms, respectively, were picked up. The coefficient of diversity of hereditary diseases (the number of nosological forms per 10 inhabitants) with different types of inheritance is higher in the Krasnodar population, as compared with the Kostroma population. The problem of similarity of the "nucleus" of autosomal-recessive disorders in Russian populations is discussed.