10 research outputs found

    Decoding the genetic relationship between Alzheimer’s disease and type 2 diabetes: potential risk variants and future direction for North Africa

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    IntroductionAlzheimer’s disease (AD) and Type 2 diabetes (T2D) are both age-associated diseases. Identification of shared genes could help develop early diagnosis and preventive strategies. Although genetic background plays a crucial role in these diseases, we noticed an underrepresentation tendency of North African populations in omics studies.Materials and methodsFirst, we conducted a comprehensive review of genes and pathways shared between T2D and AD through PubMed. Then, the function of the identified genes and variants was investigated using annotation tools including PolyPhen2, RegulomeDB, and miRdSNP. Pathways enrichment analyses were performed with g:Profiler and EnrichmentMap. Next, we analyzed variant distributions in 16 worldwide populations using PLINK2, R, and STRUCTURE software. Finally, we performed an inter-ethnic comparison based on the minor allele frequency of T2D-AD common variants.ResultsA total of 59 eligible papers were included in our study. We found 231 variants and 363 genes shared between T2D and AD. Variant annotation revealed six single nucleotide polymorphisms (SNP) with a high pathogenic score, three SNPs with regulatory effects on the brain, and six SNPs with potential effects on miRNA-binding sites. The miRNAs affected were implicated in T2D, insulin signaling pathways, and AD. Moreover, replicated genes were significantly enriched in pathways related to plasma protein binding, positive regulation of amyloid fibril deposition, microglia activation, and cholesterol metabolism. Multidimensional screening performed based on the 363 shared genes showed that main North African populations are clustered together and are divergent from other worldwide populations. Interestingly, our results showed that 49 SNP associated with T2D and AD were present in North African populations. Among them, 11 variants located in DNM3, CFH, PPARG, ROHA, AGER, CLU, BDNF1, CST9, and PLCG1 genes display significant differences in risk allele frequencies between North African and other populations.ConclusionOur study highlighted the complexity and the unique molecular architecture of North African populations regarding T2D-AD shared genes. In conclusion, we emphasize the importance of T2D-AD shared genes and ethnicity-specific investigation studies for a better understanding of the link behind these diseases and to develop accurate diagnoses using personalized genetic biomarkers

    Mutation in POLR3K causes hypomyelinating leukodystrophy and abnormal ribosomal RNA regulation

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    International audienceObjective To identify the genetic cause of hypomyelinating leukodystrophy in 2 consanguineous families. Methods Homozygosity mapping combined with whole-exome sequencing of consanguineous families was performed. Mutation consequences were determined by studying the structural change of the protein and by the RNA analysis of patients' fibroblasts. Results We identified a biallelic mutation in a gene coding for a Pol III-specific subunit, POLR3K (c.121C>T/p.Arg41Trp), that cosegregates with the disease in 2 unrelated patients. Patients expressed neurologic and extraneurologic signs found in POLR3A-and POLR3B-related leu-kodystrophies with a peculiar severe digestive dysfunction. The mutation impaired the POLR3K-POLR3B interactions resulting in zebrafish in abnormal gut development. Functional studies in the 2 patients' fibroblasts revealed a severe decrease (60%-80%) in the expression of 5S and 7S ribosomal RNAs in comparison with control. Conclusions These analyses underlined the key role of ribosomal RNA regulation in the development and maintenance of the white matter and the cerebellum as already reported for diseases related to genes involved in transfer RNA or translation initiation factors

    Multidimensional scaling plot analysis of the Tunisian subpopulation and worldwide populations.

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    <p>The plot reveals three distinct clusters showing that the Tunisian population present a close affinity with the North Africans and Europeans and distinct from South Africans and Asians. Tunisian population; Capital Tunis TU_TC, coastal city of Monastir TU_MC (AffymetrixChip 6.0 genotyping array), African ancestry in the south Western USA (ASW); a northwestern European population (CEU); the Han Chinese in Beijing, China (CHB); a Chinese population of metropolitan Denver, Colorado, USA (CHD); the Gujarati Indians in Houston, Texas, USA (GIH); the Japanese population in Tokyo, Japan (JPT); the Luhya people in Webuye, Kenya (LWK); people of Mexican ancestry living in Los Angeles, California, USA (MEX); the Maasai people in Kinyawa, Kenya (MKK); the Tuscan people of Italy (TSI); and the Yoruba in Ibadan, Nigeria (YRI); data from HapMap were retrived in March 2016. It is available by FTP: <a target="_blank">ftp://ftp.ncbi.nlm.nih.gov/hapmap/</a> and Algeria (ALG), Egyptia (EGY), Libya (LIB), Tunisia Dwiret TUN_Ber, Lebanon (LIB), Morocco South (MCS), Morocco North (MCN), Spain South (SPS), Spain North (SPN), Spain Basc (SBA),: Sub-Saharan (SAH), Canary Island (CIS); data from the literature [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0194842#pone.0194842.ref034" target="_blank">34</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0194842#pone.0194842.ref035" target="_blank">35</a>].</p