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.

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.

Keywords: Calcium and Bone; Clinical Genetics; Diabetes; Metabolic Disorders; Renal Medicine.

Figure 1

Partial pedigrees. Pedigrees of the four families demonstrate co-segregation of the p.R76W HNF4A mutation with neonatal hypoglycaemia and Fanconi syndrome. The genotype is given below each symbol where known. For each proband, age at follow-up, mutation, birth weight Z score, hypoglycaemia treatment and duration, age of diabetes diagnosis/diabetes management, age of diagnosis of Fanconi syndrome, glomerular filtration rate (GFR) (mLs/min/1.73 m²) and height Z score are provided. The mutation is reported according to the HNF4A cDNA sequence published by Chartier et al but has also been described as p.R85W according to reference sequence NM_000457.3 or p.R63W using NM_175914.3 (LRG_483). Birth weight and height Z scores are calculated from UK 1990 child growth including standard children and preterm infants. Our proband's grandfather developed diabetes at 51 years of age with a body mass index (BMI) of 30.5. He is managed with weight loss alone with a recent HbA1c of 39 mmol/mol. The mutation was present in his leukocyte DNA at 26% but it is not known if the mutation load in his pancreas is sufficient to cause his diabetes. He had no reported neonatal hypoglycaemia or Fanconi syndrome (data not shown). Neither the proband, his mother, nor her sister are currently diabetic, but they undergo surveillance using an annual oral glucose tolerance test.

Figure 2

(A) Boxplots comparing (1) urinary retinol-binding protein, (2) mean urinary amino acid Z scores, (3) urinary glucose, (4) serum urate, (5 and 6) urinary and serum calcium, (7) urinary phosphate and (8) urinary oxalate between R76W mutations and other HNF4A mutations. Boxplots demonstrate the phenotype is mutation specific by comparing patients with the mutation to patients with other HNF4A mutations. We compared analysis of fasted first-void urine and renal ultrasound scans between patients with the R76W mutation and 20 patients with other mutations in HNF4A. Medians were compared using the Mann–Whitney U Test or Fisher's exact test, and a mean urinary amino acid Z score calculated (with control data being derived from laboratory reference ranges). Other HNF4A mutations comprise: S34X, R80Q, A120D, R125W (2), R125Q, V190A, D206Y, R244W, L260P, L263P, E276Q, R303H, R303C, I314F, L332P, delEx1-7, c.466-2A>G, c.1delA, t(3;20)(p21.2;q12). (Laboratory reference ranges are shown with dashed lines (where a single line is present the reference range is below this value).). (B) Renal ultrasonographic images comparing nephrocalcinosis changes to normal kidney. Nephrocalcinosis is demonstrated by increased reflectivity of the renal pyramids, as seen in the top panel (patient heterozygous for R76W), compared to normal ultrasound images in the bottom panel (patient with balanced translocation t(3;20)(p21.2;q12) described by Gloyn et al23).

Figure 2

(A) Boxplots comparing (1) urinary retinol-binding protein, (2) mean urinary amino acid Z scores, (3) urinary glucose, (4) serum urate, (5 and 6) urinary and serum calcium, (7) urinary phosphate and (8) urinary oxalate between R76W mutations and other HNF4A mutations. Boxplots demonstrate the phenotype is mutation specific by comparing patients with the mutation to patients with other HNF4A mutations. We compared analysis of fasted first-void urine and renal ultrasound scans between patients with the R76W mutation and 20 patients with other mutations in HNF4A. Medians were compared using the Mann–Whitney U Test or Fisher's exact test, and a mean urinary amino acid Z score calculated (with control data being derived from laboratory reference ranges). Other HNF4A mutations comprise: S34X, R80Q, A120D, R125W (2), R125Q, V190A, D206Y, R244W, L260P, L263P, E276Q, R303H, R303C, I314F, L332P, delEx1-7, c.466-2A>G, c.1delA, t(3;20)(p21.2;q12). (Laboratory reference ranges are shown with dashed lines (where a single line is present the reference range is below this value).). (B) Renal ultrasonographic images comparing nephrocalcinosis changes to normal kidney. Nephrocalcinosis is demonstrated by increased reflectivity of the renal pyramids, as seen in the top panel (patient heterozygous for R76W), compared to normal ultrasound images in the bottom panel (patient with balanced translocation t(3;20)(p21.2;q12) described by Gloyn et al23).