The HNF4A R76W mutation causes atypical dominant Fanconi syndrome in addition to a β cell phenotype

Alexander Hamilton, C Bingham, TJ McDonald, PR Cook, RC Caswell, MN Weedon, RA Oram, BM Shields, M Shepherd, Carol D Inward, Julian P Hamilton-Shield, J Kohlhase, S Ellard, AT Hattersley

Research output: Contribution to journalArticle (Academic Journal)peer-review

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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.

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.
Original languageEnglish
Article number165-169
Number of pages5
JournalJournal of Medical Genetics
Volume51
Issue number3
Early online date27 Nov 2013
DOIs
Publication statusPublished - Mar 2014

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