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Cited by 63Pancreatic function and diabetesGenetic Syndromes and ImprintingDiabetes and associated disorders

Paternal allelic mutation at the Kcnq1 locus reduces pancreatic β-cell mass by epigenetic modification of Cdkn1c

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Asahara, Shun-ichiro, Etoh, Hiroaki, Inoue, Hiroyuki, Teruyama, Kyoko, Shibutani, Yuki, Ihara, Yuka, Kawada, Yukina, Bartolome, Alberto +16 more·2015·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.1422104112PMC PMC4500236
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Abstract

Significance: Recently, the potassium voltage-gated channel, KQT-like subfamily Q, member1 ( KCNQ1 ) gene has received much attention as a candidate susceptibility gene for type 2 diabetes in Asian, European, and other populations. The molecular mechanism underlying the association of KCNQ1 with the onset of type 2 diabetes has remained unclear; however, we have now found that a paternal allelic mutation of Kcnq1 results in the up-regulation of the neighboring imprinted gene cyclin-dependent kinase inhibitor 1C ( Cdkn1c ), a cell cycle inhibitor, in pancreatic β-cells of mice, with this effect being mediated by epigenetic modification of the Cdkn1c promoter. These changes seem to be responsible for the reduced pancreatic β-cell mass and impaired glucose tolerance characteristics of Kcnq1 mutant mice.

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  • It is unlikely that Kcnq1 channels contribute much to the outward current in mouse or human β-cells, and thus that the KCNQ1 locus increases T2DM risk by affecting β-cell channel activity.

    “This makes it unlikely that Kcnq1 channels contribute much to the outward current in mouse or human β-cells, and thus that the KCNQ1 locus increases T2DM risk by affecting β-cell channel activity.”

    From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [23]

    The Discussion (page unavailable) reports that loss of KCNQ1 did not significantly change insulin secretion in the mice studied, which supports a limited inference about its importance there. It does not measure outward current, and it says the opposite of the claim's human-cell inference: evidence from human islets suggests KCNQ1 plays a role in insulin secretion and warrants consideration as a type 2 diabetes risk effector. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Kcnq1/KCNQ1 is expressed at very low levels in both mouse and human β-cells, and mice lacking Kcnq1 show normal GIIS.

    “However, Kcnq1/KCNQ1 is expressed at very low levels in both mouse and human β-cells (Appendix Figure 5A) and mice lacking Kcnq1 show normal GIIS (23).”

    From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [23]

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Research works printed but not linked: 38

  1. Voight BF, et al.; MAGIC investigators; GIANT Consortium (2010) Twelve type 2 di- abetes susceptibility loci identified through large-scale association analysis. Nat Genet 42(7):579-589.
  2. Yamauchi T, et al. (2010) A genome-wide association study in the Japanese pop- ulation identifies susceptibility loci for type 2 diabetes at UBE2E2 and C2CD4A- C2CD4B. Nat Genet 42(10):864-868.
  3. Yasuda K, et al. (2008) Variants in KCNQ1 are associated with susceptibility to type 2 diabetes mellitus. Nat Genet 40(9):1092-1097.
  4. Unoki H, et al. (2008) SNPs in KCNQ1 are associated with susceptibility to type 2 di- abetes in East Asian and European populations. Nat Genet 40(9):1098-1102.
  5. Chen YH, et al. (2003) KCNQ1 gain-of-function mutation in familial atrial fibrillation. Science 299(5604):251-254.
  6. Wang Q, et al. (1996) Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias. Nat Genet 12(1):17-23.
  7. Grahammer F, et al. (2001) The cardiac K+ channel KCNQ1 is essential for gastric acid secretion. Gastroenterology 120(6):1363-1371.
  8. Grahammer F, Warth R, Barhanin J, Bleich M, Hug MJ (2001) The small conductance K+ channel, KCNQ1: Expression, function, and subunit composition in murine trachea. J Biol Chem 276(45):42268-42275.
  9. Hu C, et al. (2009) Variations in KCNQ1 are associated with type 2 diabetes and beta cell function in a Chinese population. Diabetologia 52(7):1322-1325.
  10. Jonsson A, et al. (2009) A variant in the KCNQ1 gene predicts future type 2 diabetes and mediates impaired insulin secretion. Diabetes 58(10):2409-2413.
  11. Casimiro MC, et al. (2001) Targeted disruption of the Kcnq1 gene produces a mouse model of Jervell and Lange-Nielsen Syndrome. Proc Natl Acad Sci USA 98(5):2526-2531.
  12. Lee MP, Hu RJ, Johnson LA, Feinberg AP (1997) Human KVLQT1 gene shows tissue- specific imprinting and encompasses Beckwith-Wiedemann syndrome chromosomal rearrangements. Nat Genet 15(2):181-185.
  13. Gould TD, Pfeifer K (1998) Imprinting of mouse Kvlqt1 is developmentally regulated. Hum Mol Genet 7(3):483-487.
  14. Caspary T, Cleary MA, Baker CC, Guan XJ, Tilghman SM (1998) Multiple mechanisms regulate imprinting of the mouse distal chromosome 7 gene cluster. Mol Cell Biol 18(6):3466-3474.
  15. Smilinich NJ, et al. (1999) A maternally methylated CpG island in KvLQT1 is associated with an antisense paternal transcript and loss of imprinting in Beckwith-Wiedemann syndrome. Proc Natl Acad Sci USA 96(14):8064-8069.
  16. Fitzpatrick GV, Soloway PD, Higgins MJ (2002) Regional loss of imprinting and growth deficiency in mice with a targeted deletion of KvDMR1. Nat Genet 32(3):426-431.
  17. Shin JY, Fitzpatrick GV, Higgins MJ (2008) Two distinct mechanisms of silencing by the KvDMR1 imprinting control region. EMBO J 27(1):168-178.
  18. Pandey RR, et al. (2008) Kcnq1ot1 antisense noncoding RNA mediates lineage-specific transcriptional silencing through chromatin-level regulation. Mol Cell 32(2):232-246.
  19. Matsuoka S, et al. (1995) p57KIP2, a structurally distinct member of the p21CIP1 Cdk inhibitor family, is a candidate tumor suppressor gene. Genes Dev 9(6):650-662.
  20. Mohammad F, Mondal T, Guseva N, Pandey GK, Kanduri C (2010) Kcnq1ot1 non- coding RNA mediates transcriptional gene silencing by interacting with Dnmt1. De- velopment 137(15):2493-2499.
  21. Redrup L, et al. (2009) The long noncoding RNA Kcnq1ot1 organises a lineage-specific nuclear domain for epigenetic gene silencing. Development 136(4):525-530.
  22. Yang X, et al. (2009) CDKN1C (p57) is a direct target of EZH2 and suppressed by multiple epigenetic mechanisms in breast cancer cells. PLoS ONE 4(4):e5011.
  23. Mancini-Dinardo D, Steele SJ, Levorse JM, Ingram RS, Tilghman SM (2006) Elongation of the Kcnq1ot1 transcript is required for genomic imprinting of neighboring genes. Genes Dev 20(10):1268-1282.
  24. Jacobson DA, et al. (2007) Kv2.1 ablation alters glucose-induced islet electrical ac- tivity, enhancing insulin secretion. Cell Metab 6(3):229-235.
  25. MacDonald PE, Wheeler MB (2003) Voltage-dependent K(+) channels in pancreatic beta cells: Role, regulation and potential as therapeutic targets. Diabetologia 46(8): 1046-1062.
  26. Chen H, et al. (2009) Polycomb protein Ezh2 regulates pancreatic beta-cell Ink4a/Arf expression and regeneration in diabetes mellitus. Genes Dev 23(8):975-985.
  27. Park JH, Stoffers DA, Nicholls RD, Simmons RA (2008) Development of type 2 diabetes following intrauterine growth retardation in rats is associated with progressive epi- genetic silencing of Pdx1. J Clin Invest 118(6):2316-2324.
  28. Travers ME, et al. (2013) Insights into the molecular mechanism for type 2 diabetes susceptibility at the KCNQ1 locus from temporal changes in imprinting status in hu- man islets. Diabetes 62(3):987-992.
  29. Avrahami D, et al. (2014) Targeting the cell cycle inhibitor p57Kip2 promotes adult human β cell replication. J Clin Invest 124(2):670-674.
  30. Kassem SA, et al. (2001) p57(KIP2) expression in normal islet cells and in hyperinsu- linism of infancy. Diabetes 50(12):2763-2769.
  31. Ohshige T, et al. (2011) Association of new loci identified in European genome-wide association studies with susceptibility to type 2 diabetes in the Japanese. PLoS ONE 6(10):e26911.
  32. Fadista J, et al. (2014) Global genomic and transcriptomic analysis of human pan- creatic islets reveals novel genes influencing glucose metabolism. Proc Natl Acad Sci USA 111(38):13924-13929.
  33. Shigeyama Y, et al. (2008) Biphasic response of pancreatic beta-cell mass to ablation of tuberous sclerosis complex 2 in mice. Mol Cell Biol 28(9):2971-2979.
  34. Hashimoto N, et al. (2006) Ablation of PDK1 in pancreatic beta cells induces diabetes as a result of loss of beta cell mass. Nat Genet 38(5):589-593.
  35. Matsuda T, et al. (2010) Ablation of C/EBPbeta alleviates ER stress and pancreatic beta cell failure through the GRP78 chaperone in mice. J Clin Invest 120(1):115-126.
  36. Tudurí E, Filiputti E, Carneiro EM, Quesada I (2008) Inhibition of Ca2+ signaling and glucagon secretion in mouse pancreatic alpha-cells by extracellular ATP and puri- nergic receptors. Am J Physiol Endocrinol Metab 294(5):E952-E960.
  37. Asahara S, et al. (2013) Ras-related C3 botulinum toxin substrate 1 (RAC1) regulates glucose-stimulated insulin secretion via modulation of F-actin. Diabetologia 56(5): 1088-1097.
  38. Miki T, et al. (2005) Distinct effects of glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 on insulin secretion and gut motility. Diabetes 54(4): 1056-1063.

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Authors
Asahara, S.-I., Etoh, H., Inoue, H., Teruyama, K., Shibutani, Y., Ihara, Y., Kawada, Y., Bartolome, A., Hashimoto, N., Matsuda, T., Koyanagi-Kimura, M., Kanno, A., Hirota, Y., Hosooka, T., Nagashima, K., Nishimura, W., Inoue, H., Matsumoto, M., Higgins, M. J., Yasuda, K., Inagaki, N., Seino, S., Kasuga, M., & Kido, Y.
Affiliations
  • Kobe University (JP)
  • Kanazawa University (JP)
  • Division of Medical Chemistry, Department of Biophysics, Kobe University Graduate School of Health Sciences, Hyogo 654-0142, Japan;
  • Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Hyogo 650-0017, Japan;
  • Kyoto University (JP)
  • Jichi Medical University (JP)
  • National Center for Global Health and Medicine (JP)
  • Roswell Park Comprehensive Cancer Center (US)
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2015-06-22
Volume
112
Issue
27
Pages
8332-8337
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.1422104112
PMC
PMC4500236
OpenAlex
W1526286057
Cited by
63
References
5
Citations by year
2026: 4 · 2025: 5 · 2024: 3 · 2023: 6 · 2022: 6 · 2021: 9 · 2020: 7 · 2019: 4 · 2018: 7 · 2017: 6 · 2016: 5 · 2015: 1
FWCI
6.38
Type
journal article
Language
en
Open access
Licence
www.pnas.org/site/misc/userlicense.xhtml (vor)
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • DIGITAL.CSIC (Spanish National Research Council (CSIC)) (acceptedVersion)
Funders
  • Ministry of Education, Culture, Sports, Science, and Technology (18GS0317, 22590981, 26461382, 2422900)
  • Astellas Pharma (None)
  • HHS | NIH | National Cancer Institute (2RO1 CA089426)
Topics
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Syndromes and Imprinting
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
Keywords
KCNQ1, KCNQ1OT1, CDKN1C, genomic imprinting, beta-cell mass, type 2 diabetes, paternal allele, epigenetic regulation, histone modifications, imprinted genes, non-coding RNA, pancreatic islets, cell cycle inhibitors
MeSH terms
Insulin Secretion, Alleles, Animals, Glucose, Glucose Tolerance Test, Insulin, Male, Mutation, Immunoblotting, Gene Expression, Mice, Knockout, Genomic Imprinting, Reverse Transcriptase Polymerase Chain Reaction, Inheritance Patterns, Epigenesis, Genetic, Insulin-Secreting Cells, Cyclin-Dependent Kinase Inhibitor p57, KCNQ1 Potassium Channel

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