Correspondence

NHERF1 Mutations and Responsiveness of Renal Parathyroid Hormone

N Engl J Med 2008; 359:2615-2617December 11, 2008

Article

To the Editor:

Karim et al. (Sept. 11 issue)1 report on three nonsynonymous nucleotide changes in NHERF1 (also called SLC9A3R1) — at p.L110V, p.R153Q, and p.E225K — which were found in 4 of 92 unrelated patients with nephrolithiasis or osteopenia. The change at p.L110V was also found in one of the controls; however, this person had reduced renal phosphate reabsorption, measured by dividing tubular maximal reabsorption of phosphate by the glomerular filtration rate (TmP/GFR), and the authors therefore suggest that this person was misclassified. The change at p.R153Q segregated with nephrolithiasis in two relatives of Patient 3, but like p.E225K, it was not found in the control group.

Although these findings are of great significance, two of the reported nucleotide changes have been listed as single-nucleotide polymorphisms in the National Center for Biotechnology Information dbSNP, Ensembl, and GeneCards databases for more than 2 years (Table 1Table 1Database Information Regarding Two NHERF1 Variations.).2-4 This information could suggest that these two NHERF1 variations are relatively common risk factors for nephrolithiasis or osteopenia in the general population. Alternatively, it raises the question of whether there is any relationship at all between the clinical symptoms of the patients who were studied and these polymorphisms. Further genetic and clinical investigations are warranted to address these possibilities.

Clemens Bergwitz, M.D.
Murat Bastepe, M.D., Ph.D.
Massachusetts General Hospital, Boston, MA 02114

4 References

1. 1

   Karim Z, Gerard B, Bakouh N, et al. NHERF1 mutations and responsiveness of renal parathyroid hormone. N Engl J Med 2008;359:1128-1135
   Full Text | Web of Science | Medline

2. 2

   Wheeler DL, Barrett T, Benson DA, et al. Database resources of the National Center for Biotechnology Information. Nucleic Acids Res 2006;34:D173-D180
   CrossRef | Web of Science | Medline

3. 3

   Hubbard TJ, Aken BL, Beal K, et al. Ensembl 2007. Nucleic Acids Res 2007;35:D610-D617
   CrossRef | Web of Science | Medline

4. 4

   Safran M, Chalifa-Caspi V, Shmueli O, et al. Human gene-centric databases at the Weizmann Institute of Science: GeneCards, UDB, CroW 21 and HORDE. Nucleic Acids Res 2003;31:142-146
   CrossRef | Web of Science | Medline

To the Editor:

In 2001, Prié and coworkers reported that almost one fifth of patients with nephrolithiasis and normal parathyroid function have a disorder of phosphate homeostasis characterized by reduced renal phosphate reabsorption.1 In patients with the same characteristics, we reported the presence of elevated levels of fibroblast growth factor 23 (FGF-23), a hormone regulating phosphate homeostasis.2 Karim and coworkers report the influence of NHERF1 gene mutations in the pathogenesis of this disorder of phosphate homeostasis. In the studied cohort, even after exclusion of patients with definitely elevated FGF-23 levels, all patients evaluated had FGF-23 levels within the “normal” range. This finding makes one wonder whether detectable levels of FGF-23 with reduced renal phosphate reabsorption should be considered as abnormal (or inappropriately normal).3 Further research in this direction is needed.

Domenico Rendina, M.D.
Federico II University, 80131 Naples, Italy
domenico.rendina@unina.it

Gianpaolo De Filippo, M.D.
Gaetano Rummo Hospital, 82100 Benevento, Italy

Pasquale Strazzullo, M.D.
Federico II University, 80131 Naples, Italy

3 References

1. 1

   Prie D, Ravery V, Boccon-Gibod L, Friedlander G. Frequency of renal phosphate leak among patients with calcium nephrolithiasis. Kidney Int 2001;60:272-276
   CrossRef | Web of Science | Medline

2. 2

   Rendina D, Mossetti G, De Filippo G, Cioffi M, Strazzullo P. Fibroblast growth factor 23 is increased in calcium nephrolithiasis with hypophosphatemia and renal phosphate leak. J Clin Endocrinol Metab 2006;91:959-963
   CrossRef | Web of Science | Medline

3. 3

   Endo I, Fukumoto S, Ozono K, et al. Clinical usefulness of measurement of fibroblast growth factor 23 (FGF23) in hypophosphatemic patients: proposal of diagnostic criteria using FGF23 measurement. Bone 2008;42:1235-1239
   CrossRef | Web of Science | Medline

Author/Editor Response

We agree with Bergwitz and Bastepe that two nonsynonymous nucleotide changes have been reported in a general population. On the basis of the allele frequencies of these NHERF1 variants in this population, we believe that we should have detected these variants among the 112 patients (224 alleles) with normal TmP/GFR values, if these variants were distributed independently of the TmP/GFR value. We found NHERF1 variants only among patients with low TmP/GFR values (7 of 46 patients). This very significant difference in distribution (P<0.001 by Fisher's exact test) suggests that the NHERF1 variants are associated with the phenotype of low TmP/GFR. Furthermore, experimental studies performed on renal cells in culture showed that the NHERF1 amino acid changes alter NHERF1 functionality and phosphate uptake. We think that these two lines of evidence provide support for the role of the NHERF1 variants in the decrease in TmP/GFR values in our patients.

Since FGF-23 decreases renal phosphate reabsorption and can induce hypophosphatemia, we studied patients with normal serum FGF-23 concentrations. Rendina et al. hypothesized that serum FGF-23 concentrations should be low in patients with hypophosphatemia. Undetectable FGF-23 levels are considered normal. We did not assess the serum FGF-23 concentrations in our patients according to whether the TmP/GFR values were normal or low, so we do not know whether hypophosphatemia lowered FGF-23 production. Although the serum FGF-23 concentration correlates with the serum phosphate concentration in patients with kidney disease, such a correlation has not been reported, to our knowledge, in patients with normal renal function. It is not known whether, when renal function is normal, FGF-23 concentrations are lower in patients with hypophosphatemia than in patients with normal serum phosphate levels. We agree that further studies are required to clarify this point.

Dominique Prié, M.D., Ph.D.
Hôpital Necker–Enfants Malades, Paris 75015, France
dominique.prie@inserm.fr

Gérard Friedlander, M.D., Ph.D.
Université Paris Descartes, Paris 75015, France