case_images: PMC11269260_01
case_images: Genetic analysis of SLC12A3 mutations in a Gitelman syndrome family trio.
case_images: fgene-15-1391015-g001.jpg
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case_images: F1
case_images: SLC12A3 gene: M1: c.421G>A: p.G141R, M2: c.509T>A: p.L170Q, and M3: c.704C>A: p.T235K (Figure 1). Specifically, M1 causes a glycine-to-arginine swap at amino acid position 141, M2 changes leucine to glutamine at position 170, and M3 alters threonine to lysine at position 235.
case_images: The proband's next-generation sequencing (NGS) analysis identified three heterozygous variants in the SLC12A3 gene: a missense variant (c.421G>A) resulting in the amino acid substitution p.G141R, and a second variant (c.509T>A and c.704C>A) leading to the amino acid changes p.L170Q and p.T235K, respectively. These genetic findings were confirmed by Sanger sequencing, as depicted in the electropherograms.
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case_images: F2
case_images: These mutations were subsequently confirmed by Sanger sequencing, attesting to their authenticity (Figure 2).
case_images: The protein encoded by the M2 mutation site is highly conserved (Conservation score: 0.918) and plays an important role in protein function; and the mutation reduces protein stability (Foldx prediction 1.98924). AlphaFold AI system helps us to predict the mutation protein's 3D structure (https://alphafold.ebi.ac.uk/). The family pedigree provided illustrates the distribution of these SLC12A3 variants among the members. Individuals carrying the compound heterozygous variants are indicated with marked symbols. Circles represent female family members, and squares represent male family members, with the arrow pointing to the proband. The patient's father carries M1 and M2 mutation alleles, presenting with mild hypokalemia but without clinical symptoms, and has no diabetes. The mother carries the M3 mutation yet exhibits no clinical symptoms.
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case_images: F3
case_images: These mutations constitute rare compound heterozygous variations (Figure 3).
case_images: (A) presents the results of the patient's Oral Glucose Tolerance Test (OGTT). (B.1) and (B.2) depict the changes in electrolyte levels before and after the adjustment of hypoglycemic medication during a two-year follow-up period for our patient. (C) illustrates a schematic of the ion regulation by the NCC and SGLT2 proteins in the renal tubules. The NCC protein reabsorbs sodium and chloride in renal tubules. When NCC function is impaired, compensatory mechanisms in other renal segments enhance sodium reabsorption to maintain blood volume and pressure. The effect of SGLT2 inhibitors on NCC's ion regulation during glucose lowering remains unclear.
case_images: fgene-15-1391015-g004.jpg
case_images: PMC11269260_01_fgene-15-1391015-g004.jpg
case_images: F4
case_images: Ultimately, the integration of clinical observations and genetic findings led to the diagnosis of Gitelman syndrome (GS) alongside type 2 diabetes mellitus (T2DM) in the patient (Figure 4A).