New deletion in LAMP2 causing familial Danon disease. Effect of the X-chromosome inactivation.

Danon disease (DD), a rare X-linked genetic illness with a poor prognosis, is caused by a mutation in the lysosome-associated membrane protein 2 gene (LAMP2). Three main clinical features of this pathology are cardiomyopathy, skeletal myopathy, and mental retardation. Most Danon disease mutations create premature stop codons resulting in the decrease or absence of LAMP2 protein.

Association of MIR137 With Symptom Severity and Cognitive Functioning in Belarusian Schizophrenia Patients.

MicroRNA-137 (miRNA-137; miR-137) is one of the important post-transcriptional regulators of the nervous system development, and its MIR137 gene rs1625579 polymorphism was reported to be a potential regulator for schizophrenia susceptibility. However, schizophrenia characteristics controlled by MIR137 rs1625579 polymorphism are still insufficiently understood. There were 3 groups included in the study: (a) subjects with diagnosis of schizophrenia (n = 150; 81-females, 69-males), (b) mentally healthy people (control group; n = 102; 66-females, 36-males) and (c) Belarusian indigenous male group (n = 295). Associations of rs1625579 with schizophrenia, symptom's severity and cognitive performance [by using Positive and Negative Syndrome Scale (PANSS) and Wisconsin Card Sorting Test (WCST), respectively] were studied, when compared to controls. Allele and genotype frequencies were investigated in Belarusian indigenous males. Rs1625579 displayed no association with schizophrenia in Belarusian population. Significant "symptom severity-genotype" interactions were revealed for schizophrenia patients. Patients with T/G genotype displayed lower severity of positive symptoms and general psychopathology compared to homozygous subjects. T/T genotype was associated with the highest symptom's severity. The negative symptom scores and the total PANSS-score were significantly higher in females carrying genotype T/T vs. T/G+G/G; no significant gene-phenotype associations were found in males. WCST parameters did not show any association with rs1625579 polymorphism. MIR137 rs1625579 polymorphism might be an important sex-dependent factor influencing severity of schizophrenia psychopathological manifestations. These findings also contribute to the knowledge on candidate gene effects on characteristics related to schizophrenia phenotype. As miR 137 is considered to be cancer therapeutic target, miR-137 may also explain the lower incidence of cancer in schizophrenia patients. Further studies with larger sample size are needed to confirm these novel findings.

The genetic variation in the R1a clade among the Ashkenazi Levites' Y chromosome.

Approximately 300,000 men around the globe self-identify as Ashkenazi Levites, of whom two thirds were previously shown to descend from a single male. The paucity of whole Y-chromosome sequences precluded conclusive identification of this ancestor's age, geographic origin and migration patterns. Here, we report the variation of 486 Y-chromosomes within the Ashkenazi and non-Ashkenazi Levite R1a clade, other Ashkenazi Jewish paternal lineages, as well as non-Levite Jewish and non-Jewish R1a samples. Cumulatively, the emerging profile is of a Middle Eastern ancestor, self-affiliating as Levite, and carrying the highly resolved R1a-Y2619 lineage, which was likely a minor haplogroup among the Hebrews. A star-like phylogeny, coalescing similarly to other Ashkenazi paternal lineages, ~1,743 ybp, suggests it to be one of the Ashkenazi paternal founders; to have expanded as part of the overall Ashkenazi demographic expansion, without special relation to the Levite affiliation; and to have subsequently spread to non-Ashkenazi Levites.

Three new cases of dilated cardiomyopathy caused by mutations in LMNA gene.

Three cases of delated cardiomyopathy (DCM) with conduction defects (OMIM 115200), limb girdle muscular dystrophy 1B (OMIM 159001) and autosomal dominant Emery-Dreifuss muscular dystrophy 2 (OMIM 181350), all associated with different LMNA mutations are presented. Three heterozygous missense mutations were identified in unrelated patients - p.W520R (c.1558T > C), p.T528R (с.1583С > G) and p.R190P (c.569G > C). We consider these variants as pathogenic, leading to isolated DCM with conduction defects or syndromic DCM forms with limb-girdle muscular dystrophy and Emery-Dreifuss muscular dystrophy. The mutations were not detected in the ethnically matched control group and publicly available population databases. Their de novo occurrence led to the development of the disease that was not previously detected in the extended families. Mutations at the same codons associated with laminopathies have been already reported. Differences in the clinical phenotype for p.R190P and p.T528R carrier patients are shown and compared to previous reports.

East Eurasian ancestry in the middle of Europe: genetic footprints of Steppe nomads in the genomes of Belarusian Lipka Tatars.

Medieval era encounters of nomadic groups of the Eurasian Steppe and largely sedentary East Europeans had a variety of demographic and cultural consequences. Amongst these outcomes was the emergence of the Lipka Tatars-a Slavic-speaking Sunni-Muslim minority residing in modern Belarus, Lithuania and Poland, whose ancestors arrived in these territories via several migration waves, mainly from the Golden Horde. Our results show that Belarusian Lipka Tatars share a substantial part of their gene pool with Europeans as indicated by their Y-chromosomal, mitochondrial and autosomal DNA variation. Nevertheless, Belarusian Lipkas still retain a strong genetic signal of their nomadic ancestry, witnessed by the presence of common Y-chromosomal and mitochondrial DNA variants as well as autosomal segments identical by descent between Lipkas and East Eurasians from temperate and northern regions. Hence, we document Lipka Tatars as a unique example of former Medieval migrants into Central Europe, who became sedentary, changed language to Slavic, yet preserved their faith and retained, both uni- and bi-parentally, a clear genetic echo of a complex population interplay throughout the Eurasian Steppe Belt, extending from Central Europe to northern China.

Genetic Heritage of the Balto-Slavic Speaking Populations: A Synthesis of Autosomal, Mitochondrial and Y-Chromosomal Data.

The Slavic branch of the Balto-Slavic sub-family of Indo-European languages underwent rapid divergence as a result of the spatial expansion of its speakers from Central-East Europe, in early medieval times. This expansion-mainly to East Europe and the northern Balkans-resulted in the incorporation of genetic components from numerous autochthonous populations into the Slavic gene pools. Here, we characterize genetic variation in all extant ethnic groups speaking Balto-Slavic languages by analyzing mitochondrial DNA (n = 6,876), Y-chromosomes (n = 6,079) and genome-wide SNP profiles (n = 296), within the context of other European populations. We also reassess the phylogeny of Slavic languages within the Balto-Slavic branch of Indo-European. We find that genetic distances among Balto-Slavic populations, based on autosomal and Y-chromosomal loci, show a high correlation (0.9) both with each other and with geography, but a slightly lower correlation (0.7) with mitochondrial DNA and linguistic affiliation. The data suggest that genetic diversity of the present-day Slavs was predominantly shaped in situ, and we detect two different substrata: 'central-east European' for West and East Slavs, and 'south-east European' for South Slavs. A pattern of distribution of segments identical by descent between groups of East-West and South Slavs suggests shared ancestry or a modest gene flow between those two groups, which might derive from the historic spread of Slavic people.

LMNA-related dilated cardiomyopathy.

A case of idiopathic dilated cardiomyopathy (DCM) that is likely to be associated with LMNA mutation Arg190Pro in a heterozygote is described. The features of DCM in the patient were conduction disorders, cardiac arrhythmias, progressive heart failure and minor musculoskeletal disturbances. We consider that the mutation Arg190Pro contributes to the formation of a weak nuclear lamina and diminishes muscle mechanical stability which is critical during cardiac contraction. The case report illustrates in detail the phenotypic manifestations of the novel LMNA mutation and difficulties in management related to it.

Uniparental genetic heritage of belarusians: encounter of rare middle eastern matrilineages with a central European mitochondrial DNA pool.

Ethnic Belarusians make up more than 80% of the nine and half million people inhabiting the Republic of Belarus. Belarusians together with Ukrainians and Russians represent the East Slavic linguistic group, largest both in numbers and territory, inhabiting East Europe alongside Baltic-, Finno-Permic- and Turkic-speaking people. Till date, only a limited number of low resolution genetic studies have been performed on this population. Therefore, with the phylogeographic analysis of 565 Y-chromosomes and 267 mitochondrial DNAs from six well covered geographic sub-regions of Belarus we strove to complement the existing genetic profile of eastern Europeans. Our results reveal that around 80% of the paternal Belarusian gene pool is composed of R1a, I2a and N1c Y-chromosome haplogroups - a profile which is very similar to the two other eastern European populations - Ukrainians and Russians. The maternal Belarusian gene pool encompasses a full range of West Eurasian haplogroups and agrees well with the genetic structure of central-east European populations. Our data attest that latitudinal gradients characterize the variation of the uniparentally transmitted gene pools of modern Belarusians. In particular, the Y-chromosome reflects movements of people in central-east Europe, starting probably as early as the beginning of the Holocene. Furthermore, the matrilineal legacy of Belarusians retains two rare mitochondrial DNA haplogroups, N1a3 and N3, whose phylogeographies were explored in detail after de novo sequencing of 20 and 13 complete mitogenomes, respectively, from all over Eurasia. Our phylogeographic analyses reveal that two mitochondrial DNA lineages, N3 and N1a3, both of Middle Eastern origin, might mark distinct events of matrilineal gene flow to Europe: during the mid-Holocene period and around the Pleistocene-Holocene transition, respectively.

Spectrum of genetic changes in patients with non-syndromic hearing impairment and extremely high carrier frequency of 35delG GJB2 mutation in Belarus.

The genetic nature of sensorineural hearing loss (SNHL) has so far been studied for many ethnic groups in various parts of the world. The single-nucleotide guanine deletion (35delG) of the GJB2 gene coding for connexin 26 was shown to be the main genetic cause of autosomal recessive deafness among Europeans. Here we present the results of the first study of GJB2 and three mitochondrial mutations among two groups of Belarusian inhabitants: native people with normal hearing (757 persons) and 391 young patients with non-syndromic SNHL. We have found an extremely high carrier frequency of 35delG GJB2 mutation in Belarus -5.7%. This point deletion has also been detected in 53% of the patients with SNHL. The 312del14 GJB2 was the second most common mutation in the Belarus patient cohort. Mitochondrial A1555G mt-RNR1 substitution was found in two SNHL patients (0.55%) but none were found in the population cohort. No individuals carried the A7445G mutation of mitochondrial mt-TS1. G7444A as well as T961G substitutions were detected in mitochondrial mt-RNR1 at a rate of about 1% both in the patient and population cohorts. A possible reason for Belarusians having the highest mutation carrier frequency in Europe 35delG is discussed.

Heteroplasmy and paternally oriented shift of the organellar DNA composition in barley-wheat hybrids during backcrosses with wheat parents.

Mitochondrial (mt) and chloroplast (ct) genome inheritance was studied in barley-wheat hybrids, as were their progenies obtained from backcrosses with different common wheat cultivars, by monitoring the composition of 4 mtDNA (coxI, a 5'-flanking region of cob, nad3-orf156, and 5'-upstream region of 18S/5S) and 2 ctDNA (simple-sequence repeat locus downstream of trnS and a 3'-flanking region of rbcL) loci. In male sterile F1 and BC1 plants, maternal barley mtDNA fragments were mainly detected and very low levels of paternal wheat fragments were occasionally detected by PCR in coxI, a 5'-flanking region of cob and nad3-orf156, whereas a 5'-upstream region of 18S/5S showed clear heteroplasmy, containing both maternal and paternal copies, with maternal copies prevailing. Plants showing such heteroplasmic mtDNA composition remained either semisterile or became completely sterile in the later backcross generations. Only maternal ctDNA copies were detected in these plants. In 3 stable, self-fertile, and vigourous lines obtained in the advanced backcross generations and possessing recombinant wheat nuclear genome, however, only mt- and ctDNA copies of wheat parents were detected; thus, the original alloplasmic condition appeared to be lost. Our results suggest that transmission followed by selective replication of the paternal wheat organellar DNA leads to a paternally oriented shift of the organellar DNA composition in barley-wheat hybrids, which correlates with the restoration of fertility and plant vigour. These 2 processes seem to be related to nucleocytoplasmic compatibility and to be under the control of the nuclear genome composition.

The productivity characteristics of substituted barley lines with marked chloroplast and mitochondrial genomes.

We present the effects of cytoplasm substitution on five productivity traits in an alloplasmic barley collection. 60 lines combining 5 nuclear genomes of cultivated barley varieties and 12 plasmons of two barley species (H. vulgare, H. spontaneum) displayed various effects depending on definite nuclei-cytoplasm combinations. Only four cytoplasmic genomes (W1, W4, W5, W10) significantly modified the expression of the nuclear genes controlling productivity. RAPD-PCR analysis revealed that both the mitochondrial and chloroplast DNA of the W1, W5, and W10 lines have common molecular characters distinguishing them from the cytoplasmic genomes of the other lines. The cytoplasmic genetic factors influencing the expression of "productivity" genes remain elusive.