CHCHD10 variants in amyotrophic lateral sclerosis: where Is the evidence?

Objective: After the initial report of a CHCHD10 mutation in mitochondrial disease with features resembling amyotrophic lateral sclerosis (ALS), CHCHD10 mutations have been considered to be a frequent cause for ALS. However, the exact pathogenicity and clinical significance of these mutations remain unclear. Here, we aimed to determine the role of CHCHD10 mutations in ALS. Methods: We analyzed 4,365 whole genome sequenced ALS patients and 1,832 controls from 7 different countries and examined all nonsynonymous single nucleotide variants in CHCHD10. These were tested for association with ALS, independently and in aggregate using several genetic burden tests (including sequence kernel association test [SKAT], optimal unified test [SKAT-O], and Firth logistic regression). Results: We identified 3 new variants in cases, but only 1 was ALS-specific. lso, 1 control-specific mutation was identified. There was no increased burden of rare coding mutations among ALS patients compared to controls (p=0.86, p=0.86, and p=0.88 for SKAT, SKAT-O, and Firth, respectively). The few carriers with potential pathogenic CHCHD10 mutations exhibited a slowly progressive ALS-like phenotype with atypical features such as myopathy and deafness. Interpretation: CHCHD10 mutations seem to be a far less prevalent cause of pure ALS than previously suggested, and instead appear related to more complex phenotypes. There appears to be insufficient evidence for the pathogenicity of most previously reported variants in pure ALS. This study shows that routine testing for CHCHD10 mutations in pure ALS is not recommended and illustrates the importance of sufficient genetic and functional evidence in establishing pathogenicity of genetic variants

Dimensions of water contamination in the subprovinces of Adana province, Turkey [Adana ili kırsalında su kirliliginin boyutları]

Aim: To determine the dimension of the contamination of the drinking and utility water in the touristic Bahçe district of the Karataş subprovince of Adana province, and to share our views on how to raise the quality of the water in the district. Materials and methods: In 2007 and 2008, 80 samples were taken 8 times, on a seasonal basis, from the drinking water and sea water of the Bahçe district. Eleven organic and inorganic parameters were measured and presented following a comparison with criteria values Results: Ni, Zn, Cu, Pb, NO;3;-N, COD, and phenol contamination parameters were found to be high in the stations that provide drinking water and utility water for the Bahçe district. Conclusion: This level of contamination was attributed to the extensive use of natural and artificial fertilizers and pesticide, agricultural contamination, and the fact that polluters were not at a safe distance from the stations and were particularly hazardous types of polluters. It is of the utmost importance that training be provided in order to ensure use of fertilizers and pesticides in standard amounts and at standard times. The training should be supported with warnings and inspections. © TÜBİTAK

Phenotypic and genotypic features of patients diagnosed with ALS in the city of Sakarya, Turkey

PMID = 3267169

Genotyping of methicillin resistant Staphylococcus aureus strains causing nosocomial infections by pulsed field gel electrophoresis in Adana Çukurova University Hospital [Adana Çukurova Üniversitesi Hastanesinde hastane İnfeksiyonuna yol açan metisiline dirençli Staphylococcus aureus suşlarının pulsed field jel elektroforezi yöntemi ile genotiplendirilmesi]

Objective: Methicillin resistant Staphylococcus aureus (MRSA) is one of the most important pathogens causing nosocomial infections. Genotyping epidemiologically related MRSA strains is useful in terms of determining the sources of infectious pathogens, potential carriers, ways of spread and enviromental factors and thus preventing and decreasing nosocomial infections. Pulsed field gel electrophoresis (PFGE) is accepted as the gold standard among the molecular methods used for investigation of genotypic relation. In our study, we aimed to genotype MRSA causing nosocomial infections by pulsed field gel electrophoresis. Material and Methods: In the study, genotypic relationship of 46 MRSA isolates that caused nosocomial infections in different clinics of our hospital between 2005 and 2007 were evaluated using PFGE method which genomic DNA cut by Smal enzyme. Isolates with PGFE band profiles resembling to each other 80% and above with Gel Compar II program were accepted as clonally related. Results: Forty two strains out of 46 were found to be closely related and took place in the same major "A" group while four strains were found to be unrelated. All of 12 MRSA strains isolated from reanimation clinic were found to take place in group "A" and 100% resemblance was found in eight of them. Conclusion: A single MRSA genotype was found to dominate and cause nosocomial infections in the three year period according to PFGE analysis results. © 2010 by Türkiye Klinikleri

Multiomics Analyses Identify Genes and Pathways Relevant to Essential Tremor

Introduction: The genetic factors and molecular mechanisms predisposing to essential tremor (ET) remains largely unknown. / Objective: The objective of this study was to identify pathways and genes relevant to ET by integrating multiomics approaches. / Methods: Case‐control RNA sequencing of 2 cerebellar regions was done for 64 samples. A phenome‐wide association study (pheWAS) of the differentially expressed genes was conducted, and a genome‐wide gene association study (GWGAS) was done to identify pathways overlapping with the transcriptomic data. Finally, a transcriptome‐wide association study (TWAS) was done to identify novel risk genes for ET. / Results: We identified several novel dysregulated genes, including CACNA1A and SHF. Pathways including axon guidance, olfactory loss, and calcium channel activity were significantly enriched. The ET GWGAS data found calcium ion‐regulated exocytosis of neurotransmitters to be significantly enriched. The TWAS also found calcium and olfactory pathways enriched. The pheWAS identified that the underexpressed differentially expressed gene, SHF, is associated with a blood pressure medication (P = 9.3E‐08), which is used to reduce tremor in ET patients. Treatment of cerebellar DAOY cells with the ET drug propranolol identified increases in SHF when treated, suggesting it may rescue the underexpression. / Conclusion: We found that calcium‐related pathways were enriched across the GWGAS, TWAS, and transcriptome. SHF was shown to have significantly decreased expression, and the pheWAS showed it was associated with blood pressure medication. The treatment of cells with propranolol showed that the drug restored levels of SHF. Overall, our findings highlight the power of integrating multiple different approaches to prioritize ET pathways and genes

Genome-wide association study identifies genetic factors that modify age at onset in Machado-Joseph disease

Machado-Joseph disease (MJD/SCA3) is the most common form of dominantly inherited ataxia worldwide. The disorder is caused by an expanded CAG repeat in the ATXN3 gene. Past studies have revealed that the length of the expansion partly explains the disease age at onset (AO) variability of MJD, which is confirmed in this study (Pearson's correlation coefficient R2 = 0.62). Using a total of 786 MJD patients from five different geographical origins, a genome-wide association study (GWAS) was conducted to identify additional AO modifying factors that could explain some of the residual AO variability. We identified nine suggestively associated loci (P < 1 × 10-5). These loci were enriched for genes involved in vesicle transport, olfactory signaling, and synaptic pathways. Furthermore, associations between AO and the TRIM29 and RAG genes suggests that DNA repair mechanisms might be implicated in MJD pathogenesis. Our study demonstrates the existence of several additional genetic factors, along with CAG expansion, that may lead to a better understanding of the genotype-phenotype correlation in MJD.FA and CL were funded by the Fonds de Recherche du Québec–Santé. SM is funded by FCT (CEECIND/00684/2017) and by NORTE-01-0145- FEDER-000008, supported by Norte Portugal Regional Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF). FM and LI are funded by Fundaçao de Amparo a Pesquisa do Estado de São Paulo (FAPESP, 2013/07559-3). MLSP and LBJ were funded by Conselho Nacional de Desenvolvimento Científico e Tecnológico, Brazil (CNPq) and by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES). GAR holds a Canada Research Chair in Genetics of the Nervous System and the Wilder Penfield Chair in Neurosciences

Revisiting the complex architecture of ALS in Turkey: Expanding genotypes, shared phenotypes, molecular networks, and a public variant database

PMID = 3257978