Gitelman syndrome caused by a novel hemiallelic missense mutation in SLC12A3 revealed by 16q12.2q21 microdeletion.
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ABSTRACT:
SUBMITTER: Abe Y
PROVIDER: S-EPMC7253428 | biostudies-literature | 2020
REPOSITORIES: biostudies-literature
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Gitelman syndrome caused by a novel hemiallelic missense mutation in <i>SLC12A3</i> revealed by 16q12.2q21 microdeletion.
Abe Yuki Y Yamamoto Toshiyuki T Izumita Yukie Y Tsukano Shinya S
Human genome variation 20200527
Gitelman syndrome (GS) is caused by biallelic mutations in <i>SLC12A3</i> as an autosomal recessive trait. A patient with a de novo 16q12.2q21 microdeletion showed clinical features of GS. <i>SLC12A3</i> included in the deletion was analyzed, and a rare missense variant (c.1222A>C [p.N406H]) was identified as hemizygous. Consequently, GS was caused by the revealed <i>SLC12A3</i> variant owing to chromosomal microdeletion. ...[more]
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Project description: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.
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