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The diabetic phenotype in HNF4A mutation carriers is moderated by the expression of HNF4A isoforms from the P1 promoter during fetal development

¹Institute of Biomedical and Clinical Sciences, Peninsula Medical School, Exeter, UK
²Centre for Human Development, Stem Cells & Regeneration; Human Genetics Division, University of Southampton, Southampton, UK
³Department of Clinical Medicine, University of Bergen, N-5020, Bergen, Norway
⁴Department of Paediatrics, Haukeland University Hospital, N-5021, Bergen, Norway

Objective: Mutations in the alternatively-spliced HNF4A gene cause maturity-onset diabetes of the young (MODY). We characterised the spatial and developmental expression patterns of HNF4A transcripts in human tissues and investigated their role as potential moderators of MODY phenotype.

Research Design and Methods: We measured the expression of HNF4A isoforms in human adult tissues and gestationally-staged fetal pancreas by isoform-specific real-time PCR. The correlation between mutation position and age of diagnosis or age-related penetrance was assessed in a cohort of 190 patients with HNF4A mutations.

Results: HNF4A was expressed exclusively from the P2 promoter in adult pancreas, but from 9 weeks until at least 26 weeks post conception, up to 23% of expression in fetal pancreas was of P1 origin. HNF4A4-6 transcripts were not detected in any tissue. In whole pancreas, HNF4A9 expression was greater than in islets isolated from the endocrine pancreas (relative level 22% vs 7%).

Patients with mutations in exons 9 and 10 (absent from HNF4A3, HNF4A6 and HNF4A9 isoforms) developed diabetes later than those with mutations in exons 2-8, where all isoforms were affected (40 yrs versus 24 yrs; p=0.029). Exon 9/10 mutations were also associated with a reduced age-related penetrance (53 % versus 10 % without diabetes at age 55 years (p=<0.00001).

Conclusions: We conclude that isoforms derived from the HNF4A P1 promoter are expressed in human fetal, but not adult, pancreas, and that their presence during pancreatic development may moderate the diabetic phenotype in individuals with mutations in the HNF4A gene.

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