Functional characterization of naturally occurring NR3C2 gene mutations in Italian patients suffering from pseudohypoaldosteronism type 1

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Abstract

Objective: The renal form of pseudohypoaldosteronism type 1 (PHA1) is a rare disease caused by utations in the human mineral ocorticoid receptor gene (NR3C2). Design: Aim of the study was to analyze the NR3C2 gene in three Italian patients with clinical signs of renal PHA1 and to evaluate the distribution of the -2G>C, c.538A>G, and c.722C>T single nucleotide polymorphism (SNP) pattern in the PHA1 patients and in 90 controls of the same ethnic origin. Methods: Analysis of the NR3C2 gene sequence and of the polymorphic SNP markers. Functional characterization of the detected novel NR3C2 mutations utilizing aldosterone-binding assays and reporter gene transactivation assays. Results: One novel nonsense (Y134X) and one novel frameshift (212 5delA) mutation were detected. They exhibited no aldosterone binding and no transactivation abilities. No mutation was detected in the third patient. Haploinsufficiency of NR3C2 was ruled out by microsatellite analysis in this patient. The c.722T SNP was detected in 97% of alleles in the Italian population which is signiticantly different from the general German or US population. Conclusions: Molecular analysis of the NR3C2 gene in PHA1 patients is warranted to detect novel mutations in order to clarify the underlying genetic cause, which may extend the insight into relevant functional regions of the hMR protein. The effect the different distribution of the c.722T SNP is not clear to date. Further studies are necessary to provide evidence as to a possible advantage of a less sensitive hMR in southern countries. © 2007 Society of the European Journal of Endocrinology.

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Balsamo, A., Cicognani, A., Gennari, M., Sippell, W. G., Menabò, S., Baronio, F., & Riepe, F. G. (2007). Functional characterization of naturally occurring NR3C2 gene mutations in Italian patients suffering from pseudohypoaldosteronism type 1. European Journal of Endocrinology, 156(2), 249–256. https://doi.org/10.1530/eje.1.02330

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