Mutations in the monogenic diabetes gene HNF4alpha are a novel cause of macrosomia and neonatal hyperinsulinsim. A.T. Hattersley¹, A. Steele¹, T. Barrett², K. Stals¹, J.P. Shield³, S. Ellard¹, E.R. Pearson^1,4. 1) Peninsula Medical School, Exeter, UK; 2) Birmingham Childrens' hospital, Birmingham, UK; 3) Bristol University, Bristol, UK; 4) Ninewells Medical School, Dundee, Scotland.
   Heterozygous mutations in the genes encoding the beta-cell transcription factor Hepatocyte Nuclear Factor (HNF)-4alpha are known to cause maturity onset diabetes of the young (MODY). These patients have progressive reduction in insulin secretion and present with diabetes in early adulthood. Recently a mouse with a beta cell specific deletion of HNF-4 was surprisingly shown to have lower glucose and increased insulin. We examined whether HNF-4 mutations could cause hyperinsulinaemia in man.
   Reported hypoglycaemia was assessed in 106 members of 14 HNF-4 families. We also collected birth weight as insulin is a growth factor in utero and so birth weight can be considered a bioassay of insulin secretion in utero. We compared these results with 134 members of 32 HNF-1 MODY families. Comparison was by Mann-Whitney U, Wilcoxon Signed rank and fishers exact tests.
   8 of 58 patients with heterozygous HNF-4 mutations had documented severe (<2 mmol/l) transient hypoglycaemia in infancy, with established hyperinsulinaemia in three cases. In contrast none of the 52 non mutation carriers had hypoglycaemia(p<0.01). Birth weight was increased by 790g (p<0.001) in all mutation carriers (NM) (median corrected birth weight 4450g, IQ range 3880 to 4890g) compared to non mutation (NN) family members (BW 3660g, 3340 to 3900g). 59%NM patients were macrosomic compared with 13%NN (p<0.001). In contrast there was no documented severe hypoglycaemia in HNF-1 mutation carriers and the birth weight is not increased (NM 3700g (3330 to 4200g); NN 3720g (3330 to 4360g); p=0.86).
   We conclude that HNF4- mutations are a novel cause of both transient hyperinsulinaemia of infancy and macrosomia as well as causing early-onset diabetes. This is the first beta-cell gene where a single mutation results in both increased insulin secretion in the fetus and early life and reduced insulin secretion latter in life.