Arg913Gln variation of SLC12A3 gene is associated with diabetic nephropathy in type 2 diabetes and Gitelman syndrome: a systematic review

Cruz-Cano, Eduardo De la; Jiménez–González, Cristina del C; Morales-García, Vicente; Pineda-Pérez, Conny; Tejas-Juárez, Juan G.; Rendón-Gandarilla, Francisco J.; Jiménez-Morales, Silvia; Díaz-Gandarilla, José Alfredo

doi:10.1186/s12882-019-1590-9

Cited by 14 publications

(16 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…predominately located in the ion-translocation pathway, the EC domain, the TM-TM and TMcytosol interfaces, and the NT and CT domains, likely affecting NCC folding and stability [20,55,56]. In vitro functional characterization of NCC missense mutations associated with GS revealed defective NCC plasma membrane expression, localization, and activity [57,58].…”

Section: Mutations Associated With Human Diseasesmentioning

confidence: 99%

Cation-coupled chloride cotransporters: chemical insights and disease implications

Portioli

Munevar²,

Vivo³

et al. 2021

Trends in Chemistry

View full text Add to dashboard Cite

Cation-coupled chloride cotransporters (CCCs) modulate the transport of sodium and/or potassium cations coupled with chloride anions across the cell membrane. CCCs thus help regulate intracellular ionic concentration and consequent cell volume homeostasis. This has been largely exploited in the past to develop diuretic drugs that act on CCCs expressed in the kidney. However, a growing wealth of evidence has demonstrated that CCCs are also critically involved in a great variety of other pathologies, motivating most recent drug discovery programs targeting CCCs. Here, we examine the structure-function relationship of CCCs. By linking recent high-resolution cryogenic electron microscopy (cryo-EM) data with older biochemical/functional studies on CCCs, we discuss the mechanistic insights and opportunities to design selective CCC modulators to treat diverse pathologies. Cation-coupled chloride cotransporters (CCCs): from structure to function and modulationCCCs are proteins (~130 kDa) of the subfamily of solute carrier transporters (see Glossary) 12 (SLC12) that modulate transport of sodium and/or potassium cations (Na + , K + ) and chloride anions (Cl -) across the cell membrane (Figure 1A). In humans, there are seven known electroneutral CCCs: the Na + -Clcotransporter NCC, the Na + -K + -Clcotransporters NKCC1 and NKCC2, and the K + -Clcotransporters KCC1, KCC2, KCC3, and KCC4 (Figure 1B) [1]. NCC and NKCC2 are expressed predominantly in the kidney [2]. NKCC1, KCC1, KCC3, and KCC4 are expressed throughout the body. KCC2 is expressed specifically in neurons [3]. CCCs are involved in physiological processes, including salt absorption and secretion, cell volume regulation, and intracellular Clconcentration setting [1,4]. As such, CCCs are primarily implicated in blood pressure regulation, cardiovascular and brain physiopathology, and diuresis, and are also associated with hearing and tumoral diseases (Figure 1C,D). Structure-function relationshipsCCCs mainly form homodimers, although multimeric states have been described in functional assays for N(K)CCs and KCCs [5][6][7]. Monomers for each of the CCC family members are characterized by a well-conserved transmembrane (TM) domain formed by 12 TM helices, one N-glycosylated extracellular (EC) domain, and, on the cytosolic side, the amino-terminal (NT) and the large carboxy-terminal (CT) domains (Figure 1A). All SLC12-CCC members share the same TM protein fold of the leucine transporter (LeuT [8], Box 1). The EC domain is characterized by a connecting loop between TM7 and TM8 in Na + -dependent CCCs, whereas Na + -independent CCCs have a longer loop between TM5 and TM6. The NT and EC domains are variable in amino acid length, much shorter than the CT domain, and poorly conserved among the CCC members. The EC domains contain glycosylation sites, whereas the intracellular domains contain phosphorylation sites to modulate CCC function (Figure 1A) [9]. Molecular heterogeneity is also provided by multiple CCC isoforms, generated by alternative splicing and alternative promote...

show abstract

Section: Mutations Associated With Human Diseasesmentioning

confidence: 99%

Cation-coupled chloride cotransporters: chemical insights and disease implications

Portioli

Munevar²,

Vivo³

et al. 2021

Trends in Chemistry

View full text Add to dashboard Cite

show abstract

“…Presently, the mechanism of GS with DN is still unclear, and some scholars have proposed that the dysfunction of NCC may be one of the main reasons for the risk of DN due to chronic hyperglycemia caused by insulin resistance in individuals with Type 2 Diabetes [ 9 , 10 ]. In addition, Arg913Gln variation of SLC12A3 gene is associated with DN in type 2 diabetes and GS [ 11 ]. A patient with GS and nephrotic syndrome was reported, the renal pathology revealed minimal lesions [ 7 ].…”

Section: Discussionmentioning

confidence: 99%

“…variation of SLC12A3 gene is associated with DN in type 2 diabetes and GS [11]. A patient with GS and nephrotic syndrome was reported, the renal pathology revealed minimal lesions [7].…”

mentioning

confidence: 96%

Kidney stones and moderate proteinuria as the rare manifestations of Gitelman syndrome

et al. 2021

View full text Add to dashboard Cite

Background Gitelman syndrome (GS) is an autosomal recessive inherited salt-losing tubulopathy (SLT). Here, we describe, for the first time, a case of GS without Gitelman-like features and with concomitant kidney stones, cysts and diabetic nephropathy (DN). Case presentation We described a male patient had a 19-year history of recurrent fatigue. From childhood, he had polydipsia and polyuria, paroxysmal tetany and palpitation. Serum biochemistry revealed chronic hypokalemia, metabolic alkalosis, normomagnesemia, mildly elevated Cr. Concomitant 24 h urine collection showed inappropriate renal potassium wasting, borderline hypercalciuria, moderate proteinuria consisting of major glomerular. Ultrasound of urinary tract showed bilateral and multiple kidney stones and cysts. Whole exome sequencing (WES) identified compound heterozygous mutations of SLC12A3. The unusual association of SLTs and glomerular proteinuria prompted us to perform a renal biopsy. Renal pathology showed renal involvement consistent with GS and early stage of diabetic nephropathy (DN). After treatment with KCl, magnesium oxide, perindopril and acarbose, the patient had been cured. The fatigue didn’t relapse. Conclusion GS had high variability of phenotype, GS may have no Gitelman-like features, kidney stones are not the exclusion criteria of GS. Renal biopsy should be warranted for GS patients with moderate to massive glomerular proteinuria.

show abstract

“…Bioinformatics analysis showed that if the wild-type 904Arg was replaced by the mutant allele 904Gln, the three-dimensional structure of the SLC12A3 protein will change significantly, and the Arg904Gln mutation may have important physiological significance [ 40 ]. Tanaka et al believed that the Arg904Gln gene variation in SLC12A3 could reduce the risk of diabetic nephropathy in type 2 diabetes mellitus (T2DM) [ 41 ]; however, other studies have provided evidence supporting the correlation between Arg904Gln variant and the disease development of diabetic nephropathy in patients with T2DM and GS, suggesting that this variant may be a key predictor of end-stage renal disease [ 42 , 43 ]. Several suspected pathogenic mutations were found near our newly discovered heterozygous mutant of Asp839Val (c.2516A>T): C.2490C>T (p.Thr830=), c.2495A>G (p.Asp832Gly), c.2532G>A (p.Trp844Ter), c.2510_2511del (p.Leu836_Phe837insTer), c.2514C>T (p.Asp838=), c.2521G>A (p.Gly841Ser), c.2533del (p.Leu845fs), and c.2546T>A (p.Leu849His) ( https://www.ncbi.nlm.nih.gov/clinvar ).…”

Section: Discussionmentioning

confidence: 99%

Review and Analysis of Two Gitelman Syndrome Pedigrees Complicated with Proteinuria or Hashimoto’s Thyroiditis Caused by Compound Heterozygous SLC12A3 Mutations

Zhang

Ruan

et al. 2021

BioMed Research International

View full text Add to dashboard Cite

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.

show abstract

Arg913Gln variation of SLC12A3 gene is associated with diabetic nephropathy in type 2 diabetes and Gitelman syndrome: a systematic review

Cited by 14 publications

References 53 publications

Cation-coupled chloride cotransporters: chemical insights and disease implications

Cation-coupled chloride cotransporters: chemical insights and disease implications

Kidney stones and moderate proteinuria as the rare manifestations of Gitelman syndrome

Review and Analysis of Two Gitelman Syndrome Pedigrees Complicated with Proteinuria or Hashimoto’s Thyroiditis Caused by Compound Heterozygous SLC12A3 Mutations

Contact Info

Product

Resources

About