RT Journal Article SR Electronic T1 The HNF4A R76W mutation causes atypical dominant Fanconi syndrome in addition to a β cell phenotype JF Journal of Medical Genetics JO J Med Genet FD BMJ Publishing Group Ltd SP 165 OP 169 DO 10.1136/jmedgenet-2013-102066 VO 51 IS 3 A1 Alexander J Hamilton A1 Coralie Bingham A1 Timothy J McDonald A1 Paul R Cook A1 Richard C Caswell A1 Michael N Weedon A1 Richard A Oram A1 Beverley M Shields A1 Maggie Shepherd A1 Carol D Inward A1 Julian P Hamilton-Shield A1 Jürgen Kohlhase A1 Sian Ellard A1 Andrew T Hattersley YR 2014 UL http://jmg.bmj.com/content/51/3/165.abstract AB Background Mutation specific effects in monogenic disorders are rare. We describe atypical Fanconi syndrome caused by a specific heterozygous mutation in HNF4A. Heterozygous HNF4A mutations cause a beta cell phenotype of neonatal hyperinsulinism with macrosomia and young onset diabetes. Autosomal dominant idiopathic Fanconi syndrome (a renal proximal tubulopathy) is described but no genetic cause has been defined. Methods and Results We report six patients heterozygous for the p.R76W HNF4A mutation who have Fanconi syndrome and nephrocalcinosis in addition to neonatal hyperinsulinism and macrosomia. All six displayed a novel phenotype of proximal tubulopathy, characterised by generalised aminoaciduria, low molecular weight proteinuria, glycosuria, hyperphosphaturia and hypouricaemia, and additional features not seen in Fanconi syndrome: nephrocalcinosis, renal impairment, hypercalciuria with relative hypocalcaemia, and hypermagnesaemia. This was mutation specific, with the renal phenotype not being seen in patients with other HNF4A mutations. In silico modelling shows the R76 residue is directly involved in DNA binding and the R76W mutation reduces DNA binding affinity. The target(s) selectively affected by altered DNA binding of R76W that results in Fanconi syndrome is not known. Conclusions The HNF4A R76W mutation is an unusual example of a mutation specific phenotype, with autosomal dominant atypical Fanconi syndrome in addition to the established beta cell phenotype.