The patients were mostly male and were found to have at least one allele of a splice defect on the SLC12A3 gene. Cause
The sodium chloride symporter is a protein made up of 1021 amino acids and 12 transmembrane domains. Mutations that occur on the SLC12A3 gene range from missense, nonsense, frame-shift and splice-site mutations which occur throughout the gene.Most cases of Gitelman syndrome are linked to inactivating mutations in the SLC12A3 gene, resulting in a loss of function of the thiazide-sensitive sodium-chloride co-transporter (NCCT). This genetic mutation in SLC12A3 is present in 80% of adults with Gitelman syndrome. More than 180 mutations of this transporter protein have been described. This cell membrane protein participates in the control of ion homeostasis at the distal convoluted tubule portion of the nephron. Loss of this transporter also has the indirect effect of increasing calcium reabsorption in a transcellular fashion. This has been suggested to be the result of a putative basolateral Na+/Ca2+ exchanger and apical calcium channel.When the sodium-chloride cotransporter (NCCT) is inactivated, continued action of the basolateral Na+/K+-ATPase creates a favourable sodium gradient across the basolateral membrane. This increases the reabsorption of divalent cations by secondary active transport. It is currently unknown why calcium reabsorption is increased while magnesium absorption is decreased, often leading to a low level of magnesium in the blood .A secondary effect of the inactivated sodium-chloride cotransporter is the subsequent activation of the renin-angiotensin aldosterone system (RAAS).
RAAS activation is a byproduct of the failure of the distal convoluted tubule in reuptaking electrolytes specifically sodium and chloride leading to cellular dehydration. RAAS attempts to compensate for this dehydration resulting in low serum blood potassium.A small percentage of Gitelman syndrome cases can be attributed to mutations in the CLCNKB gene. This gene is related to the function of the renal chloride channel CLC-Kb located at the basolateral membrane of cells in the thick ascending limb of the Henles loop. Genetic variations or mutations in the CLCNKB was initially linked to classic Bartter Syndrome. When mutations are not found within the SLC12A3 gene, screening can be done to rule out involvement of CLCNKB gene.Gitelman syndrome is inherited in an autosomal-recessive manner: one defective allele has to be inherited from each parent.In 2021, mutations in the tRNAs encoding Isoleucine (MT-TI) and Phenylalanine (MT-TF) in the mitochondrial DNA were described to cause Gitelman syndrome. These homomplasmic mtDNA mutations are maternally inherited. Diagnosis
Diagnosis of Gitelman syndrome can be confirmed after eliminating other common pathological sources of hypokalemia and metabolic alkalosis. A complete metabolic panel (CMP) or basic metabolic panel (BMP) can be used to evaluate serum electrolyte levels. Renin and aldosterone can be tested in the blood. Electrolyte measurement and aldosterone levels can be done via urine. The pathognomonic clinical markers include low serum levels of potassium, sodium, chloride, and magnesium in the blood as a result of urinary excretion.