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      Digenic heterozygous HNF1A and HNF4A mutations in two siblings with childhood-onset diabetes

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      Digenic_diabetes__final_paper-approved.pdf (130.9Kb)
      Date
      2013-11-01
      Author
      Shankar, RK
      Ellard, Sian
      Standiford, D
      Pihoker, C
      Gilliam, LK
      Hattersley, Andrew T.
      Dolan, LM
      Date issued
      2013-11-01
      Journal
      Pediatric Diabetes
      Type
      Article
      Language
      en
      Publisher
      Wiley-Blackwell
      Links
      http://www.ncbi.nlm.nih.gov/pubmed/23551881
      Reason for embargo
      Publisher policy
      Abstract
      Monogenic diabetes due to mutations in the transcription factor genes hepatocyte nuclear factor 1A (HNF1A) and HNF4A is characterized by islet cell antibody negative, familial diabetes with residual insulin secretion. We report two sisters with childhood onset diabetes who are both heterozygous for the most common mutation in each of two transcription factors, HNF1A, and HNF4A. The proband was diagnosed with diabetes at 7 yr of age and treated with insulin for 4 yr. Her genetic diagnosis resulted in transition to sulfonylureas for one and a half years before insulin therapy was re-initiated due to declining glycemic control. Her sister was diagnosed with diabetes at 14 yr of age, treated initially with insulin but has been well controlled on oral sulfonylurea therapy for over 2 yr. Both sisters inherited the HNF4A gene mutation R127W from their mother and the HNF1A gene mutation P291fsinsC (c.872dup) from their father. The father was diagnosed with diabetes at 45 yr of age. Their brother is heterozygous for the HNF4A R127W mutation. Both the brother and mother have normal glucose tolerance at the ages of 16 and 46 yr, respectively. Digenic inheritance of HNF1A and HNF4A mutations is very rare and has only been reported in two families where conclusive evidence for the pathogenicity of their mutations was lacking. Follow-up studies in this family co-segregating the two most commonly reported HNF1A/HNF4A mutations will be informative for understanding the effect of digenic inheritance upon phenotypic severity and response to sulfonylurea therapy.
      Funders/Sponsor
      Centers for Disease Control and Prevention.
      National Institute of Diabetes and Digestive and Kidney Diseases
      Kaiser Permanente Southern California.
      University of Colorado Denver.
      Kuakini Medical Center.
      Children's Hospital Medical Center (Cincinnati).
      University of North Carolina at Chapel Hill
      University of Washington School of Medicine.
      Wake Forest University School of Medicine.
      NIH/NCRR
      Children's Hospital and Regional Medical Center
      Colorado Pediatric General Clinical Research Center
      Barbara Davis Center at the University of Colorado at Denver
      NIH/NCRR at the University of Cincinnati
      Juvenile Diabetes Research Foundation
      Description
      This is the peer reviewed version of the article, which has been published in final form at 10.1111/pedi.12018. This article may be used for non-commercial purposes in accordance With Wiley Terms and Conditions for self-archiving.
      Citation
      Pediatric Diabetes, 2013, Vol. 14, Issue 7, pp. 535 - 538
      Grant number
      U48/CCU919219
      U01 DP000246
      U18DP002714
      U48/CCU819241-3
      U01 DP000247
      U18DP000247-06A1
      U58CCU919256, U01 DP000245
      U48/CCU519239, U01 DP000248, 1U18DP002709
      U48/CCU419249, U01 DP000254, U18DP002708-01
      U48/CCU919219, U01 DP000250, 200-2010-35171
      UL1RR029882
      M01RR00037
      M01RR00069
      DERC NIH P30 DK57516
      1UL1RR026314-01
      9-2007-1700
      PA numbers 00097, DP-05-069, DP-10-001, contract number 200-2010-35171
      DOI
      https://doi.org/10.1111/pedi.12018
      URI
      http://hdl.handle.net/10871/14544
      ISSN
      1399-543X
      Collections
      • Institute of Biomedical & Clinical Science

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