Imperial College London
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ProfessorNickOliver

Faculty of Medicine, Department of Metabolism, Digestion and Reproduction

Wynn Chair in Human Metabolism (Clinical)
 
 
 
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Contact

 

+44 (0)20 7594 1796nick.oliver

 
 
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Location

 

7S7aCommonwealth BuildingHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Misra:2020:10.2337/dc19-1843,
author = {Misra, S and hassanali, N and Bennet, A and Juszczak, A and Caswell, R and Colclough, K and Valabhji, J and Ellard, S and Oliver, N and Gloyn, A},
doi = {10.2337/dc19-1843},
journal = {Diabetes Care},
pages = {909--912},
title = {Homozygous hypomorphic HNF1A alleles are a novel cause of young-onset diabetes and result in sulphonylurea sensitive diabetes},
url = {http://dx.doi.org/10.2337/dc19-1843},
volume = {43},
year = {2020}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - 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.
AU  - Misra,S
AU  - hassanali,N
AU  - Bennet,A
AU  - Juszczak,A
AU  - Caswell,R
AU  - Colclough,K
AU  - Valabhji,J
AU  - Ellard,S
AU  - Oliver,N
AU  - Gloyn,A
DO  - 10.2337/dc19-1843
EP  - 912
PY  - 2020///
SN  - 0149-5992
SP  - 909
TI  - Homozygous hypomorphic HNF1A alleles are a novel cause of young-onset diabetes and result in sulphonylurea sensitive diabetes
T2  - Diabetes Care
UR  - http://dx.doi.org/10.2337/dc19-1843
UR  - https://care.diabetesjournals.org/content/43/4/909
UR  - http://hdl.handle.net/10044/1/76849
VL  - 43
ER  -
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