A search for mutations in the DIA1 gene in case of hereditary methemoglobinemia type I in the iakut population

In the patients with enzymopenic hereditary methemoglobinemia type I, a disease widely distributed on the territory of Yakutia, a search for the mutations in exons 3 and 4 of the DIA1 gene encoding NADH-cytochrome b5 reductase was carried out. It was shown that Yakut patients have none of three missence mutations, Arg57Gln, Leu72Pro, and Val105Met, described in case of this disease in the neighboring populations, Chinese and Japanese, inhabiting the territories south of Yakutia.     

Effect of hydrothermal conditions of permafrost soil on radial growth of larch and pine in Central Yakutia

Results of an investigation of radial growth of Larix cajanderi Mayr and Pinus sylvestris L. in Central Yakutia are presented. The time span of the constructed tree-ring chronologies is more than 200 years. Dendroclimatological analysis revealed a close relationship of tree growth on permafrost soils with climatic factors and soil hydrothermal conditions. A significant correlation of radial growth of larch and pine trees in Central Yakutia with soil temperature and moisture at various depths was found for the first time by statistical analysis.     

Analysis of the coding regions of <Emphasis Type="Italic">VEGFR3</Emphasis> and <Emphasis Type="Italic">VEGFC</Emphasis> in Milroy disease and other primary lymphoedemas

Milroy disease (hereditary lymphoedema type I, MIM 153100) is a congenital onset primary lymphoedema with autosomal dominant inheritance. Mutations in the gene, vascular endothelial growth factor receptor 3, VEGFR3 (FLT4), are known to cause Milroy disease, but there is uncertainty about the prevalence of VEGFR3 mutations in patients with primary lymphoedema and more specifically in those with a phenotype that resembles Milroy disease. This study aims to address this issue and thereby delineate the Milroy disease phenotype. Fifty-two patients with primary lymphoedema were analysed for mutations in the coding regions of VEGFR3. Patients were divided into four groups: Typical Milroy disease with family history (group I), typical Milroy disease with no family history (group II), atypical Milroy disease (group III), and complex primary lymphoedema (group IV). Results demonstrated that with rigorous phenotyping the likelihood of detecting VEGFR3 mutations is optimised. Mutation prevalence is 75% in typical Milroy patients with a family history (group I) and 68% if positive family history is not a diagnostic criterion. A positive family history is not essential in Milroy disease. The likelihood of detecting VEGFR3 mutations in patients who have a phenotype which is not typical of Milroy disease is very small (<5%). For the 22 mutation positive patients, 14 novel VEGFR3 mutations were identified, two of which were in exon 22 and one in exon 17, confirming that these exons should be included in VEGFR3 analysis. No mutations were found outside the kinase domains, showing that analysis of this part of the gene is not useful for Milroy disease patients. VEGFC, which encodes the ligand for VEGFR3, was sequenced in all patients with typical Milroy disease (groups I and II) and no mutations were identified. F. C. Connell and P. Ostergaard contributed equally to this work. An erratum to this article can be found at     

Seasonal changes in the content of photosynthetic pigments in perennial grasses of cryolithic zone

Seasonal changes in the content of photosynthetic pigments and their ratio were studied in perennial gramineous (Psathyrostachys juncea Tzvel., Elymus sibiricus L., Bromopsis inermis Leys) and equisetaceous (Equisetum variegatum Schleich. ex Web., E. scirpoides Michx.) plants grown under conditions of cryolithic zone in Central and North-East Yakutia (the Pole of Cold). Simultaneously with growth in chlorophyll (Chl) content in all the studied species of perennial grasses of Central Yakutia, a considerable increase in the content of carotenoids (Car) of the xanthophyll cycle (XC) pigments was observed with the beginning of autumn temperature fall. Similar dependence was found in horsetails of the Pole of Cold region: the content of Car was increased by 1.2–3.0 times comparing to the summer values, whereas at the same time the concentration of oxygen-containing forms increased and the ratio of Chl to xanthophylls and Car decreased. In general, horsetails had typically a lower content of Chl and Car, which was determined not only by extremely harsh climatic conditions of the region but also by specific characteristics of Equisetaceae plants. Closer to winter time, the formation of secondary Car, rhodoxanthin, was also observed in the studied horsetail species. In this case, rhodoxanthin presumably plays more important antioxidant role than XC, which can not operate at constantly low temperatures. The obtained data suggest that one of the characteristics of cold hardening of perennial grasses under conditions of cryolithic zone of Yakutia is, presumably, the high level of primary, as well as secondary, Car with most profound antioxidant properties.     

On the fauna of tachinids (Diptera,Tachinidae) from Yakutia

144 tachinid species were recorded from Yakutia, among which 29 species, e.g., Drino galii B. B., Cleonice keteli Ziegler, Anthomyiopsis nigrisquamata Zett., Eulabidogaster setifacies Rd., Leucostoma meridianum Rd., and L. simplex Fall., were found there for the first time. Peculiarities of the distribution of some steppe species in Yakutia are considered.     

Evaporation effects as reflected in freshwaters and ostracod calcite from modern environments in Central and Northeast Yakutia (East Siberia,Russia)

Taxonomical and geochemical investigations on freshwater ostracods from 15 waters in Central and Northeast (NE) Yakutia have been undertaken in order to estimate their potential usefulness in palaeoenvironmental reconstructions based on regional fossil records. Higher variability in environmental factors such as pH, electrical conductivity, and ionic content was observed in thermokarst-affected lakes in Central Yakutia than in NE Yakutia lakes. Species diversity of freshwater ostracods reached up to eight taxa per lake, mostly dominated by Candona weltneri Hartwig 1899, in Central Yakutia, whereas in NE Yakutian waters the diversity was lower and Candona muelleri jakutica Pietrzeniuk 1977 or Fabaeformiscandona inaequivalvis (Sars 1898) had highest frequencies. Coupled analyses of stable isotopes (δ¹⁸O, δ¹³C) and element ratios (Sr/Ca, Mg/Ca) were performed on both host waters and ostracod calcite, aiming to estimate the modern relationships. Correlations between host waters and ostracod calcite of single species were found for δ¹⁸O, δ¹³C and Sr/Ca and Mg/Ca ratios. The relationships between δ¹⁸O, Mg/Ca and Sr/Ca ratios and electrical conductivity (salinity) as an expression of solute concentrations in the waters mainly controlled by evaporation are more complicated but evident, and may be useful in future interpretation of geochemical data from fossil Siberian ostracods. Handling editor: K. Martens     

Population frequency and age of c.806 C>T mutation in CYB5R3 gene as cause of recessive congenital methemoglobinemia in Yakutia

Type-I recessive congenital methemoglobinemia (RCM) is a rare autosomal disease characterized by a deficiency of the soluble form of nicotineamide adenine dinucleotide (NADH)-cytochrome b5 reductase (b5R) and clinically manifests as cyanosis of skin and mucous membranes. In the Russian Federation, type-I RCM is widely disturbed in Yakutia due to the local founder effect. The molecular genetics cause of type-I RCM in Yakutia is mutation c.806C>T in the CYB5R3 gene. In this work we used 13 polymorphic markers, which flanking the CYB5R3 gene to establish the founder haplotype. The age of the mutation was estimated as about 285 ± 135 years. In this work, we have evaluated the frequency of the c.806C>T mutation in Yakutia, which averaged 55 : 1000 Yakuts. The calculated frequency of disease was 1: 1250 Yakuts.     

Unexpectedly low mutation rates in beta-myosin heavy chain and cardiac myosin binding protein genes in Italian patients with hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiac disease. Fourteen sarcomeric and sarcomere‐related genes have been implicated in HCM etiology, those encoding β‐myosin heavy chain (MYH7) and cardiac myosin binding protein C (MYBPC3) reported as the most frequently mutated: in fact, these account for around 50% of all cases related to sarcomeric gene mutations, which are collectively responsible for approximately 70% of all HCM cases. Here, we used denaturing high‐performance liquid chromatography followed by bidirectional sequencing to screen the coding regions of MYH7 and MYBPC3 in a cohort (n = 125) of Italian patients presenting with HCM. We found 6 MHY7 mutations in 9/125 patients and 18 MYBPC3 mutations in 19/125 patients. Of the three novel MYH7 mutations found, two were missense, and one was a silent mutation; of the eight novel MYBPC3 mutations, one was a substitution, three were stop codons, and four were missense mutations. Thus, our cohort of Italian HCM patients did not harbor the high frequency of mutations usually found in MYH7 and MYBPC3. This finding, coupled to the clinical diversity of our cohort, emphasizes the complexity of HCM and the need for more inclusive investigative approaches in order to fully understand the pathogenesis of this disease. J. Cell. Physiol. 226: 2894–2900, 2011. © 2011 Wiley‐Liss, Inc.     

Analysis of the Association between the HLA-DQA1 Alleles and the Steroid 21-Hydroxylase Gene Mutations in the Patients with Congenital Adrenal Hyperplasia

In 96 patients with congenital adrenal hyperplasia (CAH) and 50 healthy donors from northwestern Russia the distribution of the HLA-DQA1 alleles and the mutation spectrum and frequency at the CYP21B gene were examined. In the patients with nonclassical (NC) CAH, the distribution of the HLA-DQA1 polymorphic alleles was similar to that in the population sample. In the patients with the salt-wasting form of the disease a statistically significant decrease of the *0401 or *0501major allele frequency was observed. The prevalence of certain HLA-DQA1 genotypes, namely, HLA5, HLA3, and HLA4, was observed in the patients with the NC, salt-wasting (SW), and simple virilizing CAH, respectively. Each clinical group was characterized by a specific spectrum of clinically valuable mutations. An association between theCYP21B mutations most frequently found in case of SW and SV CAH (delB, I2splice, and I172N) and certain HLA-DQA1alleles was demonstrated. The necessity of more precise clinical diagnostics of the NC CAH cases along with detailed examination of this group for determination of the major mutations typical of the NC CAH cases from northwestern Russia is discussed.     

A comprehensive,sensitive and economical approach for the detection of mutations in the <Emphasis Type="Italic">RB1</Emphasis> gene in retinoblastoma

Retinoblastoma (Rb) is the most common primary intraocular malignancy in children. It is brought about by the mutational inactivation of both alleles of RB1 gene in the developing retina. To identify the RB1 mutations, we analysed 74 retinoblastoma patients by screening the exons and the promoter region of RB1. The strategy used was to detect large deletions/duplications by fluorescent quantitative multiplex PCR; small deletions/insertions by fluorescent genotyping of RB1 alleles, and point mutations by PCR-RFLP and sequencing. Genomic DNA from the peripheral blood leucocytes of 74 Rb patients (53 with bilateral Rb, 21 with unilateral Rb; 4 familial cases) was screened for mutations. Recurrent mutations were identified in five patients with bilateral Rb, large deletions in 11 patients (nine with bilateral Rb and two with unilateral Rb), small deletions/insertions were found in 12 patients all with bilateral Rb, and point mutations in 26 patients (14 nonsense, six splice site, five substitution and one silent change). Three mutations were associated with variable expressivity of the disease in different family members. Using this method, the detection rates achieved in patients with bilateral Rb were 44/53 (83%) and with unilateral Rb, 5/21 (23.8%). This approach may be feasible for clinical genetic testing and counselling of patients.     

Polymorphism of the (CTG)n Repeat of the Myotonin Protein Kinase Gene in Populations of the Sakha Republic (Yakutia) and Central Asia

The allele frequency distribution of the (CTG)_n repeat located in the 3′-terminal region of the myotonin protein kinase gene (DMPK) was compared for populations of Yakutia (three ethnogeographic groups of Yakuts, Evenks, Evens, Yukaghirs, and Dolgans) and Central Asia (Kazakhs, Uzbeks, and Uighurs) and other ethnic groups. The populations of the two regions proved to considerably differ from each other: features characteristic of Asian Mongoloids were more distinct in the populations of Yakutia, while the Central Asian populations were closer to European populations. The (CTG)_n allele spectrum of Yakuts was considered in connection with the high incidence of myotonic dystrophy in Yakutia. The results support the hypothesis of the founder effect for the spread of myotonic dystrophy in Yakuts. Data on the (CTG)_n polymorphism were used to estimate the phylogenetic relationships of the populations under study.__________Translated from Molekulyarnaya Biologiya, Vol. 39, No. 3, 2005, pp. 385–393.Original Russian Text Copyright © 2005 by Fedorova, Khusainova, Kutuev, Sukhomyasova, Nikolaeva, Kulichkin, Akhmetova, Salimova, Svyatova, Berezina, Platonov, Khusnutdinova.     

Haplotype analysis of oculopharyngeal muscular dystrophy (OPMD) locus in Yakutia

Oculopharyngeal muscular dystrophy (OPMD) is a hereditary neuromuscular disease with autosomal dominant and rarely with autosomal recessive inheritance types. This study included 50 patients with a clinical diagnosis of OPMD, 23 asymptomatic carriers of the mutation from 45 unrelated families, and 56 healthy relatives, as well as population samples of four ethnic groups of Yakutia: Yakuts, Evens, Evenks, Yukaghirs. It was found that the cause of OPMD development in all investigated families is the same increase in GCN repeats to 14 copies in the PABPN1 gene. The molecular structure of the (GCN)₁₄ mutant allele is (GCG)₁₀(GCA)₃GCG. The genetic variability of ten SNPs at the OPMD locus was studied in patient families and population samples. The haplotypes of OPMD were determined by a segregation analysis technique and using the EM algorithm in the groups of patients, mutation carriers, and population samples. Only one haplotype of four SNPs (ATCG) linked with the (GCN)₁₄ mutant allele was found in Yakuts and Russian patients and OPMD mutation carriers. Probably, this indicates the accumulation of mutations as a result of the founder effect.     

Marital Structure,Genetic Fitness,and the <Emphasis Type="Italic">GJB2</Emphasis> Gene Mutations among Deaf People in Yakutia (Eastern Siberia,Russia)

Autosomal recessive deafness type 1A (DFNB1A) caused by mutations in the GJB2 gene (Cx26) is the main cause of nonsyndromic hearing impairment in many populations worldwide. It is considered that widespread prevalence of DFNB1A can be due to the long tradition of intermarriages between deaf people (assortative marriages) combined with their increased social adaptation and genetic fitness after widespread introduction of sign language. For the first time, the data on mating structure and reproduction of deaf people living in Yakutia (Eastern Siberia, Russia) are presented in comparison with contribution of the GJB2 gene mutations to the etiology of hearing impairment. The relative fertility of deaf people compared to their hearing siblings is 0.78 (mean number of children 1.76 ± 0.10 and 2.24 ± 0.09 to deaf and their hearing siblings, respectively, p = 0.0018). The rate of assortative marriages among deaf people is 77.1% (81 of 105 marriages). Biallelic mutations in the GJB2 gene were found in 42.2% (43 of 102) of examined deaf people, which corresponded to diagnosis DFNB1A for these patients. A comparison of deaf marital partners by GJB2 status revealed a proportion of noncomplementary marriages (24%) in which hearing loss in both partners was caused by the presence of biallelic GJB2 gene mutations resulting in the birth of only deaf children in such couples. Thus, the set of obtained data including a relatively high genetic fitness (expressed as relative fertility) of deaf people in Yakutia in combination with a high rate of assortative marriages among them and high incidence of DFNB1A indicates a possible weakening of selection against such trait as “deafness” and a possible increase in the frequency of GJB2 mutant alleles in subsequent generations.     

Autophagy controls the pathogenicity of OPA1 mutations in dominant optic atrophy

Optic Atrophy 1 (OPA1) gene mutations cause diseases ranging from isolated dominant optic atrophy (DOA) to various multisystemic disorders. OPA1, a large GTPase belonging to the dynamin family, is involved in mitochondrial network dynamics. The majority of OPA1 mutations encodes truncated forms of the protein and causes DOA through haploinsufficiency, whereas missense OPA1 mutations are predicted to cause disease through deleterious dominant‐negative mechanisms. We used 3D imaging and biochemical analysis to explore autophagy and mitophagy in fibroblasts from seven patients harbouring OPA1 mutations. We report new genotype–phenotype correlations between various types of OPA1 mutation and mitophagy. Fibroblasts bearing dominant‐negative OPA1 mutations showed increased autophagy and mitophagy in response to uncoupled oxidative phosphorylation. In contrast, OPA1 haploinsufficiency was correlated with a substantial reduction in mitochondrial turnover and autophagy, unless subjected to experimental mitochondrial injury. Our results indicate distinct alterations of mitochondrial physiology and turnover in cells with OPA1 mutations, suggesting that the level and profile of OPA1 may regulate the rate of mitophagy.     

Discovery of two new breeding grounds of Little Curlew (Numenius minutus) outside the known breeding range in Siberia

In spring 2002 and 2003, two new small colonies of three and five pairs, respectively, of Little Curlew (Numenius minutus) were discovered in the Oimjakon Mountains (Yakutia, Russia)     

Mediterranean fever gene mutations: correlation with cytotoxic T‐lymphocyte‐associated antigen 4 gene polymorphism

Mutations in the Mediterranean fever (MEFV) gene lead to familial Mediterranean fever (FMF), a pro‐inflammatory state characterized by outbursts of inflammatory cytokines. The aims of this study were to identify the common mutations of MEFV gene in Egyptian patients with FMF, to study cytotoxic T lymphocyte associated antigen 4 (CTLA‐4) gene polymorphism and to evaluate correlations between CTLA4–1661 polymorphisms and MEFV mutations and clinical symptoms. Four hundred and twenty‐four patients with clinical pictures suspicious of FMF were enrolled in this study. Mutations in MEFV gene were confirmed by reversed hybridization. Patients with homozygous and compound heterozygous mutations and 120 healthy controls were investigated for polymorphism of ?1661 CTLA4 gene and the findings correlated with disease incidence and clinical symptoms of the disease. Ninety‐seven patients had single heterozygous mutations and 78 had compound heterozygous or homozygous MEFV gene mutations. M694I/V726A was the most common genotype (14.1%), followed by homozygous M694I. There was no statistically significant difference between patients and controls in incidence of ?1661 A/G single nucleotide polymorphism CTLA4 (P = 0.189), nor any significant correlation with any of the clinical symptoms of FMF and MEFV gene mutations.

     

Analysis of human disease genes in the context of gene essentiality

The characteristics of human disease genes were investigated through a comparative analysis with mouse mutant phenotype data. Mouse orthologs with mutations that resulted in discernible phenotypes were separated from mutations with no phenotypic defect, listing ‘phenotype’ and ‘no phenotype’ genes. First, we showed that phenotype genes are more likely to be disease genes compared to no phenotype genes. Phenotype genes were further divided into ‘embryonic lethal’, ‘postnatal lethal’, and ‘non-lethal phenotype’ groups. Interestingly, embryonic lethal genes, the most essential genes in mouse, were less likely to be disease genes than postnatal lethal genes. These findings indicate that some extremely essential genes are less likely to be disease genes, although human disease genes tend to display characteristics of essential genes. We also showed that, in lethal groups, non-disease genes tend to evolve slower than disease genes indicating a strong purifying selection on non-disease genes in this group. In addition, phenotype and no phenotype groups showed differing types of disease mutations. Disease genes in the no phenotype group displayed a higher frequency of regulatory mutations while those in the phenotype group had more frequent coding mutations, indicating that the types of disease mutations vary depending on gene essentiality. Furthermore, missense disease mutations in no phenotype genes were found to be more radical amino acid substitutions than those in phenotype genes.     

Genetic basis of Creutzfeldt-Jakob disease in the United Kingdom: a systematic analysis of predisposing mutations and allelic variation in the PRNP gene

Creutzfeldt-Jakob disease (CJD) is a transmissible neurodegenerative disorder characterized by the accumulation of aggregates of a cellular protein, PrP, in the brain. In both human and animals, genetic alterations to the gene encoding PrP (PRNP in human) modulate susceptiblity to CJD. The recent epidemic of bovine spongiform encephalopathy in the UK has raised the possibility of transmission from animal produce to humans. To provide a baseline against which to assess possible risk factors, we have determined the frequencies of predisposing mutations and allelic variants in PRNP and their relative contributions to disease. Systematic PRNP genotype analysis was performed on suspected CJD cases referred to the National Surveillance Unit in the UK over the period 1990–1993. Inspection of 120 candidate cases revealed 67 patients with definite and probable CJD, based on clinical and neuropathological criteria. No PRNP mutations were detected in any of the remaining 53 patients assessed as “non-CJD”. A disease-associated mutation in the PRNP gene was identified in nine (13.4%) definite and probable cases of CJD, a reliable estimate of the incidence of PRNP-related inherited CJD based on a prospective epidemiological series. Within the group of sporadic CJD patients (lacking PRNP mutations), we confirmed that the genotype distribution with respect to the common methionine/valine (Met/Val) polymorphism at codon 129 within PRNP was significantly different from the normal Caucasian population. The incidence of Met homozygosity at this site was more than doubled and correlated with increased susceptibility to the development of sporadic CJD. Unlike other recent studies, Val homozygosity was also confirmed to be a significant risk factor in sporadic CJD, with the relative risks for the three genotypes Met/Met:Val/Val:Met/Val being 11:4:1. Received: 18 December 1995 / Revised: 19 January 1996     

A new species and rare species of the genus <Emphasis Type="Italic">Campsicnemus</Emphasis> Walker (Diptera,Dolichopodidae) in the Russian fauna

A new species of the genus Campsicnemus Walker (C. bagachanovae Grichanov et Volfov, sp. n.) is described from Yakutia. New records of C. pusillus (Meigen, 1824) and C. varipes Loew, 1859 are given.     

Low prevalence of <Emphasis Type="Italic">MYOC</Emphasis> mutations in UK primary open-angle glaucoma patients limits the utility of genetic testing

Primary open angle glaucoma (POAG) affects 1% of people over age 40. Early detection and treatment can prevent blindness, but the disease is often asymptomatic until a late stage. Positive family history is an important risk factor and previous studies indicate that approximately 5% of POAG results from mutations in the myocilin (MYOC) gene, raising the possibility of identifying individuals genetically predisposed to glaucoma. We collected DNA samples from 426 unselected UK POAG patients and analyzed them for MYOC mutations. The Q368X mutation was found in six patients (1.4%). No other mutations were identified, suggesting that amongst patients unselected for family history, the prevalence of MYOC mutations in the UK is lower than in other populations. Genetic and glaucoma screening was offered to first-degree relatives of these six probands (group 1) and of age/sex-matched mutation-negative controls (group 2). Of 11 group-1 relatives, three carried Q368X, one of whom already had glaucoma. Notably, of the 13 relatives in both groups who were mutation negative, one was already being treated for ocular hypertension. We therefore caution against changing glaucoma surveillance regimens in such individuals and suggest that routine untargeted genetic testing for MYOC mutations in patients with POAG would be of limited value until additional significant genetic risk factors are identified.