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Homozygous hypomorphic HNF1A alleles are a novel cause of young-onset diabetes and result in sulphonylurea sensitive diabetes

  • Misra, S
  • Hassanali, N
  • Bennet, A
  • Juszczak, A
  • Caswell, R
  • Colclough, K
  • Valabhji, J
  • Ellard, S
  • Oliver, N
  • Gloyn, A
Publication Date
Jan 07, 2020
Spiral - Imperial College Digital Repository


OBJECTIVE Heterozygous loss-of-function mutations in HNF1A cause maturity-onset diabetes of the young (MODY). Affected individuals can be treated with low-dose sulphonylureas. Individuals with homozygous HNF1A mutations causing MODY have not been reported. RESEARCH DESIGN AND METHODS We phenotyped a kindred with young-onset diabetes and performed molecular genetic testing, a mixed meal tolerance test, a sulphonylurea challenge, and in vitro assays to assess variant protein function. RESULTS A homozygous HNF1A variant (p.A251T) was identified in three insulin-treated family members diagnosed with diabetes before 20 years of age. Those with the homozygous variant had low hs-CRP levels (0.2–0.8 mg/L), and those tested demonstrated sensitivity to sulphonylurea given at a low dose, completely transitioning off insulin. In silico modeling predicted a variant of unknown significance; however, in vitro studies supported a modest reduction in transactivation potential (79% of that for the wild type; P < 0.05) in the absence of endogenous HNF1A. CONCLUSIONS Homozygous hypomorphic HNF1A variants are a cause of HNF1A-MODY. We thus expand the allelic spectrum of variants in dominant genes causing diabetes.

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