المؤلفون: Biason-Lauber, Anna, Böni-Schnetzler, Marianne, Hubbard, Basil P., Bouzakri, Karim, Brunner, Andrea, Cavelti-Weder, Claudia, Keller, Cornelia, Meyer-Böni, Monika, Meier, Daniel T., Brorsson, Caroline, Timper, Katharina, Leibowitz, Gil, Patrignani, Andrea, Bruggmann, Rémy, Boily, Gino, Zulewski, Henryk, Geier, Andreas, Cermak, Jennifer M, Elliott, Peter, Ellis, James L., Westphal, Christoph, Knobel, Urs, Eloranta, Jyrki J., Kerr-Conte, Julie, Pattou, François, Konrad, Daniel, Matter, Christian M., Fontana, Adriano, Rogler, Gerhard, Schlapbach, Ralph, Regairaz, Camille, Carballido, José M., Glaser, Benjamin, McBurney, Michael W., Pociot, Flemming, Sinclair, David A., Donath, Marc Y.

المصدر: Biason-Lauber, Anna; Böni-Schnetzler, Marianne; Hubbard, Basil P.; Bouzakri, Karim; Brunner, Andrea; Cavelti-Weder, Claudia; Keller, Cornelia; Meyer-Böni, Monika; Meier, Daniel T.; Brorsson, Caroline; Timper, Katharina; Leibowitz, Gil; Patrignani, Andrea; Bruggmann, Rémy; Boily, Gino; Zulewski, Henryk; Geier, Andreas; Cermak, Jennifer M; Elliott, Peter; Ellis, James L.; . (2013). Identification of a SIRT1 mutation in a family with type 1 diabetes. Cell metabolism, 17(3), pp. 448-455. Cell Press 10.1016/j.cmet.2013.02.001

الوصف: Type 1 diabetes is caused by autoimmune-mediated β cell destruction leading to insulin deficiency. The histone deacetylase SIRT1 plays an essential role in modulating several age-related diseases. Here we describe a family carrying a mutation in the SIRT1 gene, in which all five affected members developed an autoimmune disorder: four developed type 1 diabetes, and one developed ulcerative colitis. Initially, a 26-year-old man was diagnosed with the typical features of type 1 diabetes, including lean body mass, autoantibodies, T cell reactivity to β cell antigens, and a rapid dependence on insulin. Direct and exome sequencing identified the presence of a T-to-C exchange in exon 1 of SIRT1, corresponding to a leucine-to-proline mutation at residue 107. Expression of SIRT1-L107P in insulin-producing cells resulted in overproduction of nitric oxide, cytokines, and chemokines. These observations identify a role for SIRT1 in human autoimmunity and unveil a monogenic form of type 1 diabetes.

وصف الملف: application/pdf

العلاقة: https://boris.unibe.ch/47851Test/

الإتاحة: https://doi.org/10.1016/j.cmet.2013.02.001Test
https://boris.unibe.ch/47851/1/nihms-504469.pdfTest
https://boris.unibe.ch/47851Test/

المؤلفون: Pociot, Flemming¹ fpoc@steno.dk, Karlsen, Allan E.¹, Pedersen, Claus B.², Aalund, Mogens², Nerup, Jørn¹

المصدر: American Journal of Human Genetics. Apr2004, Vol. 74 Issue 4, p647-660. 14p.

مصطلحات موضوعية: *DIABETES, *GENOMES, *ARTIFICIAL neural networks, *GENETICS, *CARBOHYDRATE intolerance, *GENES

مستخلص: Complex traits like type 1 diabetes mellitus (T1DM) are generally taken to be under the influence of multiple genes interacting with each other to confer disease susceptibility and/or protection. Although novel methods are being developed, analyses of whole-genome scans are most often performed with multipoint methods that work under the assumption that multiple trait loci are unrelated to each other; that is, most models specify the effect of only one locus at a time. We have applied a novel approach, which includes decision-tree construction and artificial neural networks, to the analysis of T1DM genome-scan data. We demonstrate that this approach (1) allows identification of all major susceptibility loci identified by nonparametric linkage analysis, (2) identifies a number of novel regions as well as combinations of markers with predictive value for T1DM, and (3) may be useful in characterizing markers in linkage disequilibrium with protective-gene variants. Furthermore, the approach outlined here permits combined analyses of genetic-marker data and information on environmental and clinical covariates. [ABSTRACT FROM AUTHOR]

المؤلفون: Bonnevie-Nielsen, Vagn¹, Field, L. Leigh² llfield@interchange.ubc.ca, Lu, Shao², Zheng, Dong-Jun¹, Li, Min¹, Martensen, Pia M.³, Nielsen, Thomas B.⁴, Beck-Nielsen, Henning⁴, Yu-Lung Lau⁵, Pociot, Flemming⁶

المصدر: American Journal of Human Genetics. Apr2005, Vol. 76 Issue 4, p623-633. 11p.

مصطلحات موضوعية: *GENETICS, *INFECTION, *ENZYMES, *IMMUNE response, *ADENOSINES, *RNA, *CHILDREN, *NUCLEOTIDES

مستخلص: It is likely that human genetic differences mediate susceptibility to viral infection and virus-triggered disorders. OAS genes encoding the antiviral enzyme 2′5′-oligoadenylate synthetase (2′5′AS) are critical components of the innate immune response to viruses. This enzyme uses adenosine triphosphate in 2′-specific nucleotidyl transfer reactions to synthesize 2′,5′-oligoadenylates, which activate latent ribonuclease, resulting in degradation of viral RNA and inhibition of virus replication.We showed elsewhere that constitutive (basal) activity of 2′5′AS is correlated with virus-stimulated activity. In the present study, we asked whether constitutive activity is genetically determined and, if so, by which variants. Analysis of 83 families containing two parents and two children demonstrated significant correlations between basal activity in parent-child pairs (P<.0001 ) and sibling pairs (P=.0044 ), but not spousal pairs, suggesting strong genetic control of basal activity. We next analyzed association between basal activity and 15 markers across the OAS gene cluster. Significant association was detected at multiple markers, the strongest being at an A/G single-nucleotide polymorphism at the exon 7 splice-acceptor site (AG or AA) of the OAS1 gene. At this unusual polymorphism, allele G had a higher gene frequency in persons with high enzyme activity than in those with low enzyme activity (0.44 vs. 0.20;P=3×10-11 ). Enzyme activity varied in a dose-dependent manner across the GG, GA, and AA genotypes (tested by analysis of variance; P=1×10-14 ). Allele generates the previously described p46 enzyme isoform, whereas allele A ablates the splice site and generates a dual-function antiviral/proapoptotic p48 isoform and a novel p52 isoform. This genetic polymorphism makes OAS1 an excellent candidate for a human gene that influences host susceptibility to viral infection. [ABSTRACT FROM AUTHOR]

المؤلفون: Lie, Benedicte A., Todd, John A., Pociot, Flemming, Nerup, Jorn, Akselsen, Hanne E., Joner, Geir, Dahl-Jorgensen, Knut, Ronningen, Kjersti S., Thorsby, Erik, Undlien, Dag E.

المصدر: American Journal of Human Genetics. Mar1999, Vol. 64 Issue 3. 2 Diagrams, 2 Charts.

مصطلحات موضوعية: *DIABETES, *HLA histocompatibility antigens, *IR genes

مستخلص: Investigates the predisposition to type 1 diabetes linked to the human leukocyte antigen complex. Inclusion of non-class II gene in the predisposition; Characterization of type 1 diabetes; Analysis of extended major histocompatibility complex haplotypes.