title: The HNF4A R76W mutation causes atypical dominant Fanconi syndrome in addition to a β cell phenotype.
abstract: 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.
  
  
  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.
authors.affiliation: Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, Devon, UK.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Hamilton
authors.forename: Coralie
authors.initials: C
authors.lastname: Bingham
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: McDonald
authors.forename: Paul R
authors.initials: PR
authors.lastname: Cook
authors.forename: Richard C
authors.initials: RC
authors.lastname: Caswell
authors.forename: Michael N
authors.initials: MN
authors.lastname: Weedon
authors.forename: Richard A
authors.initials: RA
authors.lastname: Oram
authors.forename: Beverley M
authors.initials: BM
authors.lastname: Shields
authors.forename: Maggie
authors.initials: M
authors.lastname: Shepherd
authors.forename: Carol D
authors.initials: CD
authors.lastname: Inward
authors.forename: Julian P
authors.initials: JP
authors.lastname: Hamilton-Shield
authors.forename: Jürgen
authors.initials: J
authors.lastname: Kohlhase
authors.forename: Sian
authors.initials: S
authors.lastname: Ellard
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Hattersley
mesh_terms: D005198:Fanconi Syndrome / Q000000981:diagnostic imaging / Q000235:genetics* / Q000378:metabolism; D005260:Female; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics*; D009397:Nephrocalcinosis / Q000000981:diagnostic imaging; D010641:Phenotype; D014463:Ultrasonography
chemical_list: C496592:HNF4A protein, human; D051557:Hepatocyte Nuclear Factor 4
keywords: Calcium and Bone; Clinical Genetics; Diabetes; Metabolic Disorders; Renal Medicine