Gitelman syndrome A loss of NCC function is associated with Gitelman syndrome, an autosomic recessive disease characterized by salt wasting and low blood pressure, hypokalemic metabolic alkalosis, hypomagnesemia and hypocalciuria. Over a hundred different mutations in the NCC gene have been described as causing Gitelman syndrome, including nonsense, frameshift, splice site and missense mutations. Two different types of mutations exist within the group of missense mutations causing loss of NCC function. Type I mutations cause a complete loss of NCC function, in which the synthesized protein is not properly glycosylated. NCC protein harboring type I mutations is retained in the endoplasmic reticulum and cannot be trafficked to the cell surface. Type II mutations cause a partial loss of NCC function in which the cotransporter is trafficked to the cell surface but has an impaired insertion in the plasma membrane. NCC harboring type II mutations have normal kinetic properties but are present in lower amounts at the cell surface, resulting in a decreased uptake of<unk>  and<unk> . NCC harboring type II mutations is still under control of its modulators and can still increase or decrease its activity in response to stimuli, whereas type I mutations cause a complete loss of function and regulation of the cotransporter. However, in some patients with Gitelman's syndrome, no mutations in the NCC gene have been found despite extensive genetic work-up. Hypertension and blood pressure NCC has also been implicated to play a role in control of blood pressure in the open population, with both common polymorphisms and rare mutations altering NCC function, renal salt reabsorption and, presumably, blood pressure. Individuals with rare mutations in genes responsible for salt control in the kidney, including NCC, have been found to have a lower blood pressure than controls. NCC harboring these mutations has a lower function than wild-type cotransporter although some mutations found in individuals in the open population seem to be less deleterious to cotransporter function than mutations in individuals with Gitelman's syndrome. Furthermore, heterozygous carriers of mutations causing Gitelman syndrome (i.e. individuals who have a mutation in one of the two alleles and do not have the disease) have a lower blood pressure than non-carriers in the same family. Pseudohypoaldosteronism type II Type II pseudohypoaldosteronism (PHA2), also known as Gordon's syndrome, is an autosomal dominant disease in which there is an increase in NCC activity leading to short stature, increased blood pressure, increased serum K+ levels, increased urinary calcium excretion and hyperchloremic metabolic acidosis. However, PHA2 is not caused by mutations within the NCC gene, but by mutations in NCC regulators WNK1 and WNK4. Patients respond well to treatment with thiazide-type diuretics.
Sodium-chloride symporter
Sulfate transporter
Thiamine transporter 1
Carboxylate transporter
Band 3 anion transport protein
Norepinephrine transporter
Zinc transporter 8
Phosphorylase kinase, alpha 1