Gitelman's syndrome: towards genotype-phenotype correlations?

Abstract

Gitelman's syndrome (GS) is a salt-losing tubulopathy characterized by hypokalemic alkalosis with hypomagnesemia and hypocalciuria. The disease is associated with inactivating mutations in the SLC12A3 gene that codes for the thiazide-sensitive Na+-Cl- cotransporter (NCCT) that is expressed in the apical membrane of the cells lining the distal convoluted tubule (DCT). GS is relatively frequent, and more than 100 mutations scattered through SLC12A3 have been identified thus far. Although the disease is recessively inherited, up to 40% of patients are found to carry only a single mutation, instead of being compound heterozygous or homozygous. The phenotype of GS is highly heterogeneous in terms of age at presentation, and nature/severity of the biochemical abnormalities and clinical manifestations. This phenotypical heterogeneity is observed not only between all patients harbouring SLC12A3 mutations but also among family members or patients with identical mutations. In this review, we discuss the potential explanations for the failure to identify mutant alleles in SLC12A3, as well as the different mechanisms that can account for the inter- and intra-familial phenotype variability in GS, including genetic heterogeneity, position and nature of the mutations, functional consequences, compensatory mechanisms, and modifying genes.