Differential Expression of Several miRNAs and the Host Genes AATK and DNM2 in Leukocytes of Sporadic ALS Patients.

Genetic studies have managed to explain many cases of familial amyotrophic lateral sclerosis (ALS) through mutations in several genes. However, the cause of a majority of sporadic cases remains unknown. Recently, epigenetics, especially miRNA studies, show some promising aspects. We aimed to evaluate the differential expression of 10 miRNAs, including miR-9, miR-338, miR-638, miR-663a, miR-124a, miR-143, miR-451a, miR-132, miR-206, and let-7b, for which some connection to ALS was shown previously in ALS culture cells, animal models or patients, and in three miRNA host genes, including C1orf61 (miR-9), AATK (miR-338), and DNM2 (miR-638), in leukocyte samples of 84 patients with sporadic ALS. We observed significant aberrant dysregulation across our patient cohort for miR-124a, miR-206, miR-9, let-7b, and miR-638. Since we did not use neurological controls we cannot rule out that the revealed differences in expression of investigated miRNAs are specific for ALS. Nevertheless, the group of these five miRNAs is worth of additional research in leukocytes of larger cohorts from different populations in order to verify their potential association to ALS disease. We also detected a significant up-regulation of the AAKT gene and down-regulation of the DNM2 gene, and thus, for the first time, we connected these with sporadic ALS cases. These findings open up new research toward miRNAs as diagnostic biomarkers and epigenetic processes involved in ALS. The detected significant deregulation of AAKT and DNM2 in sporadic ALS also represents an interesting finding. The DNM2 gene was previously found to be mutated in Charcot-Marie-Tooth neuropathy-type CMT2M and centronuclear myopathy (CNM). In addition, as recent studies connected AATK and frontotemporal dementia (FTD) and DNM2 and hereditary spastic paraplegia (HSP), these two genes together with our results genetically connect, at least in part, five diseases, including FTD, HSP, Charcot-Marie-Tooth (type CMT2M), CNM, and ALS, thus opening future research toward a better understanding of the cell biology involved in these partly overlapping pathologies.

Clinical and genetic heterogeneity in Slovenian patients with BEST disease.

PURPOSE: To determine the spectrum of BEST1 mutations and to study the phenotype in Slovenian families with Best vitelliform macular dystrophy (BVMD) to identify genotype-phenotype correlations. METHODS: Twenty patients from five families underwent the ophthalmological examination including electrooculogram (EOG; N = 17), fundus autofluorescence imaging (N = 16) and optical coherence tomography (N = 14). Mutational screening was performed by direct DNA sequencing of the BEST1 gene. RESULTS: Mutation c.43G>C (p.Gly15Arg) was detected in three patients from family M presenting with different clinical stages of Best disease. Mutation c.313G>C (p.Arg105Gly) was found in families K, ST, S, B and was associated with incomplete clinical penetrance and variable retinal changes, including extramacular and multifocal lesions. In three patients from family K, an atypical form of BVMD was observed; there were additional peripheral lesions outside of the vascular arcades in addition to the typical macular lesions. Multiple alterations between the vitelliruptive and pseudohypopyon stages over a period of 11 years were seen in one patient. CONCLUSION: Two previously unreported disease-associated variants in the BEST1 gene (p.Gly15Arg and p.Arg105Gly) were found in Slovenian patients with Best disease. Our data expand the mutation spectrum of the BEST1 gene and further support the broad phenotypic variability observed clinically and with optical coherence tomography (OCT) and AF imaging.

Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis.

To elucidate the genetic architecture of amyotrophic lateral sclerosis (ALS) and find associated loci, we assembled a custom imputation reference panel from whole-genome-sequenced patients with ALS and matched controls (n = 1,861). Through imputation and mixed-model association analysis in 12,577 cases and 23,475 controls, combined with 2,579 cases and 2,767 controls in an independent replication cohort, we fine-mapped a new risk locus on chromosome 21 and identified C21orf2 as a gene associated with ALS risk. In addition, we identified MOBP and SCFD1 as new associated risk loci. We established evidence of ALS being a complex genetic trait with a polygenic architecture. Furthermore, we estimated the SNP-based heritability at 8.5%, with a distinct and important role for low-frequency variants (frequency 1-10%). This study motivates the interrogation of larger samples with full genome coverage to identify rare causal variants that underpin ALS risk.

Genetic analysis of amyotrophic lateral sclerosis in the Slovenian population.

Amyotrophic lateral sclerosis (ALS) is a complex fatal neurodegenerative disease characterized by progressive degeneration and loss of upper motor neurons in the cerebral cortex and lower motor neurons in brainstem and spinal cord. We established the frequencies of mutations in 4 major ALS-associated genes, SOD1, TARDBP, FUS, and C9ORF72 in a representative cohort of 85 Slovenian patients with sporadic form of ALS. Pathogenic massive hexanucleotide repeat expansion mutation in C9ORF72 was detected in 5.9% of patients and was the most common cause of the disease. In the remaining 3 genes, we identified 4 changes in 3 patients, p.Val14Met in SOD1, silent mutation p.Arg522Arg in FUS, and p.Gly93Cys in SOD1 together with a novel synonymous variant c.990A>G (p.Leu330Leu) in TARDBP gene, respectively. This study represents the first genetic screening of major causative genes for ALS in a cohort of sporadic ALS patients from Slovenia and is according to our knowledge the first such study in Slavic population. Overall, we genetically characterized 8.2% sporadic ALS patients.

The paternal perspective of the Slovenian population and its relationship with other populations.

BACKGROUND: The Slovenian territory is geographically positioned between the Alps, the Adriatic Sea, the Pannonian basin and the Dinaric Mountains and, as such, has served as a passageway for different populations over different periods of time. Turbulent historic events and the diverse geography of the region have produced a diverse contemporary population whose genetic analysis could provide insight into past demographic events. AIM: The aim of this study was to analyse Y-chromosome biallelic and STR markers in a Slovenian population from five different regions. SUBJECTS AND METHODS: A total of 42 Y-chromosomal biallelic markers and 17 Y-STRs were genotyped in 399 individuals from five different Slovenian regions. RESULTS: The analysis of Y-chromosome markers revealed 29 different haplogroups in the Slovenian population, with the most common being R1a1a, R1b, I2a1 and I1. Analysis of the genetic affiliations between different populations revealed strong affiliations of the Slovenian gene pool with West Slavic populations. CONCLUSION: Analysis of Y-chromosomal markers in five Slovenian regions revealed a diverse genetic landscape. Slovenian population display close genetic affiliations with West Slavic populations. The homogenous genetic strata of the West Slavic populations and the Slovenian population suggest the existence of a common ancestral Slavic population in central European region.