Genetic analysis of mice strains with variable serum sodium concentrations identifies the Nalcn sodium channel as a novel player in osmoregulation

Abstract

Hyponatremia and hypernatremia are disturbances of the tightly regulated osmobalance and are common electrolyte disorders in hospitalized patients. Despite their high clinical importance, only few susceptibility genes for these disorders are known. Therefore, to identify novel genes involved in the (patho-)physiology of osmoregulation, we used haplotype association mapping on 27 inbred mouse strains and determined serum sodium levels. We identified a total of five loci, of which the interval on chromosome 14 (123.5–123.7 Mb) showed the strongest correlation (Score = 4.53 p=2.98×10-5) and contained only one known gene, named Nalcn. Further characterization of Nalcn identified three distinct haplotypes with significantly different serum sodium levels of 153.4 (± 3.2), 157.9 (± 4.8) and 164.0 (± 3.9) mmol/L (p<0.05). Furthermore, we found that the T allele of one SNP was associated with an age-dependent increase in serum sodium concentration from 153.8±4.7 at 6 months to 158.6±4.9 mmol/l at 18 months. The association of Nalcn with serum sodium levels was confirmed by analysis of Nalcn heterozygous knockout mice which displayed increased concentrations as compared to wildtype littermates (149.1 ± 0.8 vs. 146.5 ± 0.7; P < 0.02). Our study demonstrates that Nalcn associates with serum sodium concentrations in mice and indicates that Nalcn is an important novel player in osmoregulation.