Based on published studies of this polymorphism in SLC12A3 and the features of the proband's father, we postulate that this polymorphism modifies the phenotype of Bartter syndrome in the proband to thiazide resistance.
Patients with renal diseases associated with salt-losing tubulopathies categorized as Gitelman and classic form of Bartter syndrome have undergone genetic screening for possible mutation capture in two different genes: SLC12A3 and CLCNKB.
Conversely, impaired function of the Na+,K+,2Cl- cotransporter (NKCC2), the renal outer medullary K+ channel (ROMK1), and the renal epithelial Cl- channel ClCKb/Barttin causes Bartter syndrome and defective Na+,Cl+ cotransporter (NCCT) Gitelman syndrome, salt-wasting disorders with hypotension.
Neonatal Bartter's syndrome is caused by mutations of NKCC2 or ROMK, classic Bartter's syndrome by mutations of ClC-Kb, Bartter's syndrome associated with sensorineural deafness is due to mutations of BSND, Gitelman's syndrome to mutations of NCCT and Bartter's syndrome associated with autosomal dominant hypocalcemia is linked to mutations of CASR.
The renal-specific Na-Cl cotransporter (NCC) and Na-K-2Cl cotransporter (NKCC2) are involved in Gitelman and Bartter syndrome, respectively, autosomal recessive forms of metabolic alkalosis.
Gitelman's syndrome, caused by loss of function mutations in the Na-Cl cotransporter of the distal convoluted tubule (NCCT), features inherited hypokalemic alkalosis with so-called "normal" blood pressure.
The hypocalciuric, hypomagnesemic variant of Bartter syndrome (Gitelman syndrome), presents in early adulthood with predominantly musculoskeletal symptoms and is due to mutations in the gene encoding the Na-Cl cotransporter (NCCT).