Electrolyte Blood Press.  2016 Jun;14(1):16-19. 10.5049/EBP.2016.14.1.16.

A Pedigree with c.179 Cytosine to Threonine Missense Mutation of SLC12A3 Gene Presenting Gitelman's Syndrome

• Kim Y
• Kang SS
• Park WY
• Jin K
• Kim DK
• Han S

• KMID: 2328426
• DOI: http://doi.org/10.5049/EBP.2016.14.1.16

Abstract

A 42-year-old man came to the hospital presenting chest discomfort and general weakness. He had come to the hospital with the same symptoms 3 months ago and 12 years prior. His laboratory test showed hypokalemia, hypomagnesemia and hypocalciuria. The arterial blood gas analysis showed hypochloremic metabolic alkalosis. He had an ultrasonography guided renal biopsy, the result was normal at light microscopy and immunofluorescence microscopy. However, a special stain for Na-Cl cotransporter was weakly expressed compared with the control. The patient and his family underwent genetic sequencing about the SLC12A3 gene. He had a homozygous mutation in the 179th nucleotide of Exon 1 on the SLC12A3 gene (p.Thr60Met) and his parents and sisters were diagnosed as carrier state of Gitelman's syndrome (GS). GS is an inherited tubular disorder which presents mild hypokalemia, hypomagnesemia and hypocalciuria. Since the symptoms and laboratory results are not severe, it can go unnoticed by physicians. Herein we present a family with GS, diagnosed by genetic sequencing.

Keyword

Gitelman's syndrome; SLC12A3 gene; Hypokalemia; Hypomagnesemia

MeSH Terms

Adult
Alkalosis
Biopsy
Blood Gas Analysis
Carrier State
Cytosine*
Exons
Gitelman Syndrome*
Humans
Hypokalemia
Microscopy
Microscopy, Fluorescence
Mutation, Missense*
Parents
Pedigree*
Siblings
Solute Carrier Family 12, Member 3
Thorax
Threonine*
Ultrasonography
Cytosine
Threonine

Figure

• 

  Fig. 1 Immonohistochemistry of Na-Cl cotransporter in renal biopsy specimens in patient (B) showed more weakly immunostained than control (A) (Original magnification, ×400).

• 

  Fig. 2 The polyacrylamide gel electrophoresis of the SLC12A3 gene SSCP profiles in Gitelman's syndrome. A homozygous mutation revealed two of new line (arrow) and heterozygous mutation revealed only one. The patient is diagnosed as GS and his family is carrier of GS. Abbreviations: N; normal control, P; patient, F1; father, F2; mother, F3; old sister, F4; first younger sister, F5; second younger sister, SSCP; single strand conformational polymorphism, GS; Gitelman's syndrome.

• 

  Fig. 3 (A) DNA sequence of SLC12A3 gene presents homozygous mutation of c.179C>T in patient, (B) and heterozygous mutation of c.179C>T in patient's family.

• 

  Fig. 4 A pedigree analysis presented patient's parents and his 3 sisters were carrier too. The potassium level of all carriers were over 3.5mEq/L and they didn't have any clinical symptoms. Abbreviations: P, patient; F1, father; F2, mother; F3, old sister; F4, first younger sister; F5, second younger sister; GS, Gitelman's syndrome.

Reference

1. Melander O, Orho-Melander M, Bengtsson K, et al. Genetic variants of thiazide-sensitive NaCl-cotransporter in Gitelman's syndrome and primary hypertension. Hypertension. 2000; 36:389–394. PMID: 10988270.

2. Simon DB, Nelson-Williams C, Bia MJ, et al. Gitelman's variant of Bartter's syndrome, inherited hypokalaemic alkalosis, is caused by mutations in the thiazide-sensitive Na-Cl cotransporter. Nat Genet. 1996; 12:24–30. PMID: 8528245.

3. Luo J, Yang X, Liang J, Li W. A pedigree analysis of two homozygous mutant Gitelman syndrome cases. Endocr J. 2015; 62:29–36. PMID: 25273610.

4. Gennari FJ. Hypokalemia. N Engl J Med. 1998; 339:451–458. PMID: 9700180.

5. Gitelman HJ, Graham JB, Welt LG. A new familial disorder characterized by hypokalemia and hypomagnesemia. Trans Assoc Am Physicians. 1966; 79:221–235. PMID: 5929460.

6. Li C, Zhou X, Han W, et al. Identification of two novel mutations in SLC12A3 gene in two Chinese pedigrees with Gitelman syndrome and review of literature. Clin Endocrinol (Oxf). 2015; 83:985–993. PMID: 25990047.

7. Maki N, Komatsuda A, Wakui H, et al. Four novel mutations in the thiazide-sensitive Na-Cl co-transporter gene in Japanese patients with Gitelman's syndrome. Nephrol Dial Transplant. 2004; 19:1761–1766. PMID: 15069170.

8. Shao L, Lang Y, Wang Y, et al. High-frequency variant p.T60M in NaCl cotransporter and blood pressure variability in Han Chinese. Am J Nephrol. 2012; 35:515–519. PMID: 22627394.

9. Lee JW, Lee J, Heo NJ, Cheong HI, Han JS. Mutations in SLC12A3 and CLCNKB and Their Correlation with Clinical Phenotype in Patients with Gitelman and Gitelman-like Syndrome. J Korean Med Sci. 2016; 31:47–54. PMID: 26770037.

10. Gamba G. Molecular physiology and pathophysiology of electroneutral cation-chloride cotransporters. Physiol Rev. 2005; 85:423–493. PMID: 15788703.

11. Reissinger A, Ludwig M, Utsch B, et al. Novel NCCT gene mutations as a cause of Gitelman's syndrome and a systematic review of mutant and polymorphic NCCT alleles. Kidney Blood Press Res. 2002; 25:354–362. PMID: 12590198.

12. Shao L, Ren H, Wang W, et al. Novel SLC12A3 mutations in Chinese patients with Gitelman's syndrome. Nephron Physiol. 2008; 108:29–36.