β-cell genes and diabetes: molecular and clinical characterization of mutations in transcription factors

Timothy M. Frayling (Lead / Corresponding author), Julie C. Evans, Michael P. Bulman, Ewan Pearson, Lisa Allen, Katharine Owen, Coralie Bingham, Michael Hannemann, Maggie Shepherd, Sian Ellard, Andrew T. Hattersley

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214 Citations (Scopus)

Abstract

β-Cell transcription factor genes are important in the pathophysiology of the β-cell, with mutations in hepatocyte nuclear factor (HNF)-1α, HNF-4α, insulin promoter factor (IPF)-1, HNF-1β, and NeuroD1/BETA2, all resulting in early-onset type 2 diabetes. We assessed the relative contribution of these genes to early-onset type 2 diabetes using linkage and sequencing analysis in a cohort of 101 families (95% U.K. Caucasian). The relative distribution of the 90 families fitting maturity-onset diabetes of the young (MODY) criteria was 63% HNF-1α, 2% HNF-4α, 0% IPF-1, 1% HNF-1β, 0% NeuroD1/ BETA2, and 20% glucokinase. We report the molecular genetic and clinical characteristics of these patients including 29 new families and 8 novel HNF-1α gene mutations. Mutations in the transactivation domain are more likely to be protein truncating rather than result in amino acid substitutions, suggesting that a relatively severe disruption of this domain is necessary to result in diabetes. Mutations in the different transcription factors result in clinical heterogeneity. IPF-1 mutations are associated with a higher age at diagnosis (42.7 years) than HNF-1α (20.4 years), HNF-1β (24.2 years), or HNF-4α (26.3 years) gene mutations. Subjects with HNF-1β mutations, in contrast to the other transcription factors, frequently present with renal disease. A comparison of age at diagnosis between subjects with different types and locations of HNF-1α mutations did not reveal genotype-phenotype correlations. In conclusion, mutations in transcription factors expressed in the β-cell are the major cause of MODY, and the phenotype clearly varies with the gene that is mutated. There is little evidence to indicate that different mutations within the same gene have different phenotypes.

Original languageEnglish
Pages (from-to)S94-S100
Number of pages7
JournalDiabetes
Volume50
Issue numberSuppl. 1
DOIs
Publication statusPublished - 22 Feb 2001

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    Frayling, T. M., Evans, J. C., Bulman, M. P., Pearson, E., Allen, L., Owen, K., Bingham, C., Hannemann, M., Shepherd, M., Ellard, S., & Hattersley, A. T. (2001). β-cell genes and diabetes: molecular and clinical characterization of mutations in transcription factors. Diabetes, 50(Suppl. 1), S94-S100. https://doi.org/10.2337/diabetes.50.2007.S94