Novel compound heterozygous mutation of SLC12A3 in Gitelman syndrome co-existent with hyperthyroidism: A case report and literature review

Abstract

Background: Gitelman syndrome (GS) is a rare inherited autosomal recessive tubulopathy, characterized clinically by hypokalemia, hypomagnesemia, hypocalciuria, and metabolic alkalosis, and is caused by an inactivating mutation in SLC12A3. GS is prone to misdiagnosis when occurring simultaneously with hyperthyroidism. It is important to consider the possibility of other diseases when hyperthyroidism is combined with hypokalemia, which is difficult to correct.

Case summary: A female patient with hyperthyroidism complicated with limb weakness was diagnosed with thyrotoxic hypokalemic periodic paralysis for 4 mo. However, the patient's serum potassium level remained low despite sufficient potassium replacement and remission of hyperthyroidism. GS was confirmed by whole exome and Sanger sequencing. Gene sequencing revealed compound heterozygous mutations of c.488C>T (p.Thr163Met), c.2612G>A (p.Arg871His), and c.1171_1178dupGCCACCAT (p.Ile393fs) in SLC12A3. Protein molecular modeling was performed to predict the effects of the identified missense mutations. All three mutations cause changes in protein structure and may result in abnormal protein function. All previously reported cases of GS coexisting with autoimmune thyroid disease are reviewed.

Conclusion: We have identified a novel compound heterozygous mutation in SLC12A3. The present study provides new genetic evidence for GS.

Keywords: Case report; Gene sequencing; Gitelman syndrome; Hyperthyroidism; Hypokalemia; SLC12A3.

Figure 1

Pedigree diagram showing proband (arrow) and segregation of SLC12A3.

Figure 2

Sanger sequencing images of pedigree mutation type in SLC12A3. The sequence diagram from the first to the fourth row represents the mother, father, proband, and son or daughter, respectively. A: The NM_000339.2:c.488C>T(p.Thr163Met) (indicated by the red arrow) is a heterozygous missense mutation in exon 3; B: The NM_000339.2:c.1171_1178dupGCCACCAT(p.Ile393fs) (indicated by the red arrow) is a heterozygous frameshift mutation in exon 9; C: The NM_000339.2:c.2612G>A(p.Arg871His) (indicated by the red arrow) is a heterozygous missense mutation in exon 22.

Figure 3

Schematic presentation of the structure of SLC12A3. A: Thr163 and Arg871 are highly conserved amino acids in various species (the locations colored yellow); B: Overview of the locations of Thr163 and Arg871 in the global three-dimensional structure of the protein. Thr163 and Arg871 are shown in green spheres, and the global protein structure is shown in the cartoon model; C and D: The mutation Ile393fs causes missing of some protein regions and domains (magenta), and transfer of MPPLAPAW* novel sequence (cyan); E and F: Analysis of changes in hydrogen bonds for the Thr163Met mutation. The key amino acids are shown as sticks and H-bonds are shown as red dotted line. One H-bond is destroyed when Thr163 is replaced by Met; G and H: The mutation Arg871His will cause large changes in the H-bond network, destruction of H-bond interaction with Asp841 and Tyr975, and generation of a new interaction with Glu901.

Figure 4

Hospital discharge follow-up results for serum electrolyte levels. The abscissa represents the date (format: Day/month/year). The double ordinates represent serum potassium level (the red line) and magnesium level (the blue line), respectively.