Long-term Clinical Course after Living Kidney Donation by a Patient with Gitelman Syndrome Harboring a Compound Heterozygous Mutation of the SLC12A3 Gene.
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SUBMITTER: Kamejima S
PROVIDER: S-EPMC8188029 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundGitelman syndrome (GS) is an autosomal recessive disorder caused by genic mutations of SLC12A3 (Solute carrier family 12 member 3), which encodes the Na-Cl cotransporter (NCC), and presents with characteristic metabolic abnormalities, including hypokalemia, metabolic alkalosis, hypomagnesemia, and hypocalciuria. In this study, we report a case of a GS pedigree, including analysis of GS-associated gene mutations.MethodsWe performed next-generation sequencing analysis and Sanger sequencing to explore the SLC12A3 mutations in a GS pedigree that included a 35-year-old female patient with GS and five family members within three generations. Furthermore, we summarized their clinical manifestations and analyzed laboratory parameters related to GS.ResultsThe female proband (the patient with GS) presented with intermittent fatigue and transient periods of tetany, along with significant hypokalemia, hypomagnesemia, and hypocalciuria. All other members of the pedigree had normal laboratory results without obvious GS-related symptoms. Genetic analysis of the SLC12A3 gene identified two novel missense mutations (c.1919A > G, p.N640S in exon 15; c.2522A > G, p.D841G in exon 21) in the patient with GS. Moreover, we demonstrated that her mother, younger maternal uncle, and cousin were carriers of one mutation (c.1919A > G), and her father was the carrier of the other (c.2522A > G).ConclusionThis is the first report of these two novel pathogenic variants of SLC12A3 and their contribution to GS. Further functional studies are particularly warranted to explore the underlying molecular mechanisms.
| S-EPMC5789536 | biostudies-literature
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.
| S-EPMC8128541 | biostudies-literature
Project description:BACKGROUND:Gitelman syndrome (GS) is a rare autosomal recessive renal tubular disease, caused by mutations in the SLC12A3 gene, which encodes the renal thiazide-sensitive Na/Cl cotransporter (NCCT) in the distal renal tubule. CASE PRESENTATION:A 23-year-old woman was admitted with limb numbness, recurrent tetany and palpitation. Laboratory tests showed hypokalemic alkalosis, hypomagnesemia, hypocalcemia and secondary hyperaldosteronism, as well as hypocalciuria and transient decreased PTH. Next-generation sequencing detected a novel homozygous mutations c.2039delG in the SLC12A3 gene, and her father and children were all heterozygous carriers. CONCLUSION:We reported a case of GS with a novel homozygous frame-shift mutation of SLC12A3, and reviewed recent literatures about diagnosis, differential diagnosis and treatments. Hypocalcemia in Gitelman syndrome is rare, and may be related to inhibited PTH secretion induced by hypomagnesemia.
| S-EPMC6296056 | biostudies-literature
Project description:BackgroundGitelman syndrome (GS) is an autosomal recessive tubulopathy caused by mutations of the SLC12A3 gene. It is characterized by hypokalemic metabolic alkalosis, hypomagnesemia and hypocalciuria. It is universally known that both hypokalemia and hypomagnesemia can influence insulin secretion and insulin resistance, but the exact mechanisms require further study. We identified a novel deletion variant of the SLC12A3 gene and discussed the appropriate hypoglycemic drugs in Gitelman syndrome (GS) patients with type 2 diabetes.Case presentationA 55-year-old diabetic female patient was hospitalized for evaluation because of paroxysmal general weakness and numbness of extremities for one year. We suspected that she was suffering from GS by initial estimation. Direct Sanger sequencing was used to analyze the causative gene SLC12A3 of GS. Oral glucose tolerance test (OGTT) was carried out to assess the glucose metabolism and insulin resistance status. Genetic analysis revealed that she was a compound heterozygote for a recurrent missense mutation c.179C > T and a novel deletion c.1740delC in SLC12A3, thus her diagnosis of GS was confirmed. The patient was treated with potassium chloride (3.0 g/d) and magnesium chloride (element magnesium 350 mg/d) on the basis of initial treatment of diabetes with hypoglycemic drug (Repaglinide, 3.0 mg/day). However, she developed frequent hypoglycemia after one week. OGTT showed that her glucose metabolism and insulin resistance much improved after potassium and magnesium supplemental therapy. Then we changed the hypoglycemic agent to a dipeptidyl peptidase-4 (DPP-4) inhibitor (Trajenta 5 mg/d), since then her blood glucose level remained normal during two-year of follow-up.ConclusionWe have identified a novel deletion of the SLC12A3 gene and discussed the appropriate hypoglycemic drugs in Gitelman syndrome (GS) patients with type 2 diabetes. We suggested that attention need to be paid to blood glucose monitoring in GS patients, especially when hypokalemia and hypomagnesemia are corrected. Besides, the insufficient blood volume and serum electrolyte disturbance should also be taken into consideration in the selecting hypoglycemic drugs for GS patients.
| S-EPMC8336329 | biostudies-literature
Project description:BACKGROUND:Gitelman syndrome is a rare salt-losing renal tubular disorder associated with mutation of SLC12A3 gene, which encodes the Na-Cl co-transporter (NCCT). Gitelman syndrome is characterized by hypokalemia, metabolic alkalosis, hypomagnesemia, hypocalciuria, and renin-angiotensin-aldosterone system (RAAS) activation. Different SLC12A3 variants may lead to phenotypic variability and severity. METHODS:In this study, we reported the clinical features and genetic analysis of a Chinese pedigree diagnosed with Gitelman syndrome. RESULTS:The proband exhibited hypokalaemia, hypomagnesemia, metabolic alkalosis, but hypercalciuria and kidney stone formation. The increased urinary calcium excretion made it confused to Bartter syndrome. The persistent renal potassium wasting resulted in renal tubular lesions, and might affect urinary calcium reabsorption and excretion. Genetic analysis revealed mutations of SLC12A3 gene with c.433C?>?T (p.Arg145Cys), c.1077C?>?G (p.Asn359Lys), and c.1666C?>?T (p.Pro556Ser). Potential alterations of structure and function of NCCT protein due to those genetic variations of SLC12A3 are predicted. Interestingly, one sibling of the proband carried the same mutant sites and exhibited similar clinical features with milder phenotypes of hypokalemia and hypomagnesemia, but hypocalciuria rather than hypercalciuria. Family members with at least one wild type copy of SLC12A3 had normal biochemistry. With administration of spironolactone, potassium chloride and magnesium supplement, the serum potassium and magnesium were maintained within normal ranges. CONCLUSIONS:In this study, we identified compound mutations of SLC12A3 associated with varieties of clinical features. Further efforts are needed to investigate the diversity in clinical manifestations of Gitelman syndrome and its correlation with specific SLC12A3 mutations.
| S-EPMC7409507 | biostudies-literature
Project description: Not available
| S-EPMC8292201 | biostudies-literature
Project description:Gitelman syndrome (GS) is caused by biallelic mutations in SLC12A3 as an autosomal recessive trait. A patient with a de novo 16q12.2q21 microdeletion showed clinical features of GS. SLC12A3 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 SLC12A3 variant owing to chromosomal microdeletion.
| S-EPMC7253428 | biostudies-literature
Project description:Gitelman syndrome (GS) is a rare autosomal recessively inherited salt-wasting tubulopathy associated with mutations in the SLC12A3 gene, which encodes for NaCl cotransporter (NCC) in the kidney.In this report, we describe two siblings from a Sri Lankan non-consanguineous family presenting with hypokalaemia associated with renal potassium wasting, hypomagnesemia, hypocalciuria and hypereninemic hyperaldosteronism with normal blood pressure. Genetic testing showed that both were homozygotes for a novel missense mutation in exon 10 of the SLC12A3 gene [NM_000339.2, c.1276A?>?T; p.N426Y], which has not previously been reported in the literature in association with GS. Their mother was a heterozygous carrier for the same mutation. The father was not alive at the time of testing. This novel mutation extends the spectrum of known SLC12A3 gene mutations and further supports the allelic heterogeneity of GS. Interestingly both siblings had young onset Diabetes with strong family history.These findings have implications in providing appropriate genetic counseling to the family with regard to the risk associated with inbreeding, the detection of carrier/presymptomatic relatives. It further expands the known spectrum of genotypic and phenotypic characteristics of Gitelman syndrome.
| S-EPMC5406964 | biostudies-literature
Project description:Gitelman syndrome (GS) is an autosomal recessive disorder characterized by alkalosis, hypokalemia, and hypomagnesemia. Although hundreds of genetic variants associated with GS have been reported, many of them are categorized as of uncertain significance in ClinVar. Here, we describe a pediatric GS patient from a three-generation family whose mother and maternal grandmother were asymptomatic. The proband was a 16-year-old Japanese girl with muscle weakness and continuous hypokalemic metabolic alkalosis. The patient, her mother, and her maternal grandmother were compound heterozygous for, and each expressing a different combination of, previously reported SLC12A3variants in GS patients. The mother and the maternal grandmother had no symptoms related to GS, and blood gas tests showed that the blood potassium levels and venous pH were within normal limits; however, the venous blood HCO3- levels were slightly elevated. The phenotypic effect of missense mutations is difficult to evaluate, and accumulation of genotypic data with accurate phenotyping, including those of "healthy" and "asymptomatic" individuals in various ethnic populations, will improve the genetic diagnosis of GS.
| S-EPMC7443650 | biostudies-literature
Project description:Gitelman syndrome is a rare, recessively inherited disease characterized by chronic hypokalemia and hypomagnesemia as a result of defective electrolyte co-transport at the level of the distal convoluted tubule of the kidney. Here, we present the first report of a patient with Gitelman syndrome who developed multiple neoplasia including colorectal polyposis, synchronous colorectal cancers, recurrent breast fibroadenomata and a desmoid tumor. Whole-exome sequencing confirmed germline compound heterozygous mutations of c.179C > T and c.1326C > G in SLC12A3, and in addition, identified a monoallelic germline c.934-2A > G splice site mutation in MUTYH. In vitro, magnesium deficiency potentiated oxidative DNA damage in lymphoblastoid cell lines derived from the same patient. We postulate that monoallelic MUTYH mutations may manifest in the presence of cooperative non-genetic mechanisms, in this case possibly magnesium deficiency from Gitelman syndrome.
| S-EPMC7501863 | biostudies-literature