Title: The genetic spectrum of Gitelman(-like) syndromes
Abstract: Purpose of review Gitelman syndrome is a recessive salt-wasting disorder characterized by hypomagnesemia, hypokalemia, metabolic alkalosis and hypocalciuria. The majority of patients are explained by mutations and deletions in the SLC12A3 gene, encoding the Na + -Cl − -co-transporter (NCC). Recently, additional genetic causes of Gitelman-like syndromes have been identified that should be considered in genetic screening. This review aims to provide a comprehensive overview of the clinical, genetic and mechanistic aspects of Gitelman(-like) syndromes. Recent findings Disturbed Na + reabsorption in the distal convoluted tubule (DCT) is associated with hypomagnesemia and hypokalemic alkalosis. In Gitelman syndrome, loss-of-function mutations in SLC12A3 cause impaired NCC-mediated Na + reabsorption. In addition, patients with mutations in CLCKNB , KCNJ10 , FXYD2 or HNF1B may present with a similar phenotype, as these mutations indirectly reduce NCC activity. Furthermore, genetic investigations of patients with Na + -wasting tubulopathy have resulted in the identification of pathogenic variants in MT-TI , MT-TF , KCNJ16 and ATP1A1 . These novel findings highlight the importance of cell metabolism and basolateral membrane potential for Na + reabsorption in the DCT. Summary Altogether, these findings extend the genetic spectrum of Gitelman-like electrolyte alterations. Genetic testing of patients with hypomagnesemia and hypokalemia should cover a panel of genes involved in Gitelman-like syndromes, including the mitochondrial genome.