Abstract
Gitelman syndrome (GS) is an autosomal recessive inherited salt-losing renal tubular disease, which is caused by a pathogenic mutation of SLC12A3 encoding thiazide-sensitive Na-Cl cotransporter, which leads to disturbance of sodium and chlorine reabsorption in renal distal convoluted tubules, resulting in phenotypes such as hypovolemia, renin angiotensin aldosterone system (RAAS) activation, hypokalemia, and metabolic alkalosis. In this study, two GS families with proteinuria or Hashimoto's thyroiditis were analyzed for genetic-phenotypic association. Sanger sequencing revealed that two probands carried SLC12A3 compound heterozygous mutations, and proband A carried two pathogenic mutations: missense mutation Arg83Gln, splicing mutation, or frameshift mutation NC_000016.10:g.56872655_56872667 (gcggacatttttg>accgaaaatttt) in exon 8. Proband B carries two missense mutations: novel Asp839Val and Arg904Gln. Both probands manifested hypokalemia, hypomagnesemia, hypocalcinuria, metabolic alkalosis, and RAAS activation; in addition, the proband A exhibited decreased urinary chloride, phosphorus, and increased magnesium ions excretion, complicated with Hashimoto's Thyroiditis, while the proband B exhibited enhanced urine sodium excretion and proteinuria. The older sister of proband B with GS also had Hashimoto's thyroiditis. Electron microscopy revealed swelling and vacuolar degeneration of glomerular epithelial cells, diffuse proliferation of mesangial cells and matrix, accompanied by a small amount of low-density electron-dense deposition, and segmental fusion of epithelial cell foot processes in proband B. Light microscopy showed mild mesangial hyperplasia in the focal segment of the glomerulus, hyperplasia, and hypertrophy of juxtaglomerular apparatus cells, mild renal tubulointerstitial lesions, and one glomerular sclerosis. So, long-term hypokalemia of GS can cause kidney damage and may also be susceptible to thyroid disease.
Highlights
Gitelman syndrome (GS) is an autosomal recessive hereditary salt-losing renal tubular disease
GS is inherited in an autosomal recessive mode, and its pathogenic gene is the SLC12A3 gene (MIM:600968; NC_000016.10), which is located on human chromosome 16q13 and consists of 26 independent exons
The SLC12A3 mutation leads to structural changes and/or dysfunctions of NaCl cotransporter (NCCT) located in the distal convoluted tubules (DCT) cortex; the reabsorption of NaCl in the DCT is reduced, and the decrease of sodium reabsorption capacity leads to an excessive exchange of sodium ions through
Summary
Gitelman syndrome (GS) is an autosomal recessive hereditary salt-losing renal tubular disease. Gitelman reported three familial diseases characterized by hypokalemia, hypomagnesemia, hypochloremic alkalosis, and hypocalciuria in 1966, and the syndrome was named after him [1]. In Asia, the prevalence of GS has significantly increased to 10.3 per 10000 people [4], and mutations may be as high as 3% [3]. GS is inherited in an autosomal recessive mode, and its pathogenic gene is the SLC12A3 gene (MIM:600968; NC_000016.10), which is located on human chromosome 16q13 and consists of 26 independent exons [5]. A variety of pathogenic mutations have been discovered, including nonsense mutations, missense mutations, frameshift mutations, deletions, insertions, and splice site mutations [6]. The hot spot mutation site is not yet known
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