Functional Analyses of HNF1A-MODY Variants Refine the Interpretation of Identified Sequence Variants.

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  • Additional Information
    • Source:
      Publisher: Oxford University Press Country of Publication: United States NLM ID: 0375362 Publication Model: Print Cited Medium: Internet ISSN: 1945-7197 (Electronic) Linking ISSN: 0021972X NLM ISO Abbreviation: J Clin Endocrinol Metab Subsets: MEDLINE
    • Publication Information:
      Publication: 2017- : New York : Oxford University Press
      Original Publication: Springfield, Ill. : Charles C. Thomas
    • Subject Terms:
      Mutation*; Biomarkers/*analysis ; Diabetes Mellitus, Type 1/*pathology ; Diabetes Mellitus, Type 2/*pathology ; Hepatocyte Nuclear Factor 1-alpha/*genetics; Adult ; Diabetes Mellitus, Type 1/genetics ; Diabetes Mellitus, Type 1/metabolism ; Diabetes Mellitus, Type 2/genetics ; Diabetes Mellitus, Type 2/metabolism ; Female ; Follow-Up Studies ; Humans ; Male ; Phenotype ; Prognosis
    • Abstract:
      Context: While rare variants of the hepatocyte nuclear factor-1 alpha (HNF1A) gene can cause maturity-onset diabetes of the young (HNF1A-MODY), other variants can be risk factors for the development of type 2 diabetes. As has been suggested by the American College of Medical Genetics (ACMG) guidelines for variant interpretation, functional studies provide strong evidence to classify a variant as pathogenic.
      Objective: We hypothesized that a functional evaluation can improve the interpretation of the HNF1A variants in our Czech MODY Registry.
      Design, Settings, and Participants: We studied 17 HNF1A variants that were identified in 48 individuals (33 female/15 male) from 20 Czech families with diabetes, using bioinformatics in silico tools and functional protein analyses (transactivation, protein expression, DNA binding, and nuclear localization).
      Results: Of the 17 variants, 12 variants (p.Lys120Glu, p.Gln130Glu, p.Arg131Pro, p.Leu139Pro, p.Met154Ile, p.Gln170Ter, p.Glu187SerfsTer40, p.Phe215SerfsTer18, p.Gly253Arg, p.Leu383ArgfsTer3, p.Gly437Val, and p.Thr563HisfsTer85) exhibited significantly reduced transcriptional activity or DNA binding (< 40%) and were classified as (likely) pathogenic, 2/17 variants were (likely) benign and 3/17 remained of uncertain significance. Functional analyses allowed for the reclassification of 10/17 variants (59%). Diabetes treatment was improved in 20/29 (69%) carriers of (likely) pathogenic HNF1A variants.
      Conclusion: Functional evaluation of the HNF1A variants is necessary to better predict the pathogenic effects and to improve the diagnostic interpretation and treatment, particularly in cases where the cosegregation or family history data are not available or where the phenotype is more diverse and overlaps with other types of diabetes.
      (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: [email protected].)
    • Grant Information:
      293574 International ERC_ European Research Council
    • Contributed Indexing:
      Keywords: ACMG classification; HNF1A-MODY; functional study; hepatocyte nuclear factor-1 alpha variants; reclassification
    • Accession Number:
      0 (Biomarkers)
      0 (HNF1A protein, human)
      0 (Hepatocyte Nuclear Factor 1-alpha)
    • Subject Terms:
      Mason-Type Diabetes
    • Publication Date:
      Date Created: 20200205 Date Completed: 20210104 Latest Revision: 20210924
    • Publication Date:
      20221213
    • Accession Number:
      10.1210/clinem/dgaa051
    • Accession Number:
      32017842