ArticleDiabetes2008
Diabetes susceptibility in the Canadian Oji-Cree population is moderated by abnormal mRNA processing of HNF1A G319S transcripts.
Article in Diabetes, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed, 29 citations in OpenAlex.
- Stem Cell-Derived β Cells: A Versatile Research Platform to Interrogate the Genetic Basis of β Cell Dysfunction.International journal of molecular sciences · 2022Review
- HNF1A：From Monogenic Diabetes to Type 2 Diabetes and Gestational Diabetes Mellitus.Frontiers in endocrinology · 2022Review
- Decreased GLUT2 and glucose uptake contribute to insulin secretion defects in MODY3/HNF1A hiPSC-derived mutant β cells.Nature communications · 2021Article
- The Common p.R114W HNF4A Mutation Causes a Distinct Clinical Subtype of Monogenic Diabetes.Diabetes · 2016Article
- Developmental origins of type 2 diabetes in aboriginal youth in Canada: it is more than diet and exercise.Journal of nutrition and metabolism · 2012Article
- Relative expression of a dominant mutated ABCC8 allele determines the clinical manifestation of congenital hyperinsulinism.Diabetes · 2012Article
- HNF1A G319S variant, active cigarette smoking and incident type 2 diabetes in Aboriginal Canadians: a population-based epidemiological study.BMC medical genetics · 2011Article
- Assessing the association of the HNF1A G319S variant with C-reactive protein in Aboriginal Canadians: a population-based epidemiological study.Cardiovascular diabetology · 2010Article
- Complex Genetics of Type 2 Diabetes and Effect Size: What have We Learned from Isolated Populations?The review of diabetic studies : RDSReview
Corrections and comments
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Authors and funding
5 authors at 3 institutions in 2 countries.
Funding
Abstract
objectiveThe G319S HNF1A variant is associated with an increased risk of type 2 diabetes in the Canadian Oji-Cree population. We hypothesized that the variant site at the 3' end of exon 4 might influence splicing and characterized mRNA transcripts to investigate the mutational mechanism underlying this susceptibility to diabetes. RESEARCH DESIGN AND
methodsWe established lymphoblastoid cell lines from a G319S homozygote and controls. HNF1A transcripts were characterized in the cell lines and pancreatic tissue by sequence analysis of RT-PCR products and quantification using real-time PCR. Susceptibility to mRNA surveillance was investigated using cycloheximide.
resultsFull-length G319S mRNA accounted for 24% of mRNA transcripts in the homozygous G319S cell line. A novel isoform lacking the terminal 12 bases of exon 4 was upregulated (55% of mRNA transcripts) compared with control cell lines (33%) and human pancreatic tissue (17%). Two abnormal transcripts present only in the G319S cell line included premature termination codons as a result of the inclusion of seven nucleotides from intron 4 or the deletion of exon 8. Cycloheximide treatment increased the levels of both transcripts.
conclusionsThe G319S variant results in the production of two abnormal transcripts and an alteration in the relative balance of normal splicing products. This is predicted to lead to a reduction in total HNF1A transcript levels, but residual hepatocyte nuclear factor-1alpha protein activity in G319S homozygotes may still reach up to 66% of normal levels. A combination of abnormal splicing and reduced activity of the G319S protein may explain the diabetes susceptibility.
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Registered trials
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