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A novel SLC12A3 gene homozygous mutation of Gitelman syndrome in an Asian pedigree and literature review

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Abstract

Objectives

Gitelman syndrome (GS) is an autosomal recessive disease characterized by hypokalemic metabolic alkalosis in combination with significant hypomagnesemia and hypocalciuria which is caused by mutations in the SLC12A3 gene. In this study, we reported a case of GS pedigree and reviewed pertinent literature so as to explore the relationship between clinical characteristics and genotype meanwhile provide recommendations for the diagnosis and treatment of GS.

Design and methods

This is a pedigree-based genetic study of GS and 11 members from one family were included. We summarized their clinical features, analyzed laboratory parameters related to GS and SLC12A3 gene.

Results

The proband experienced intermittent severe symptoms of weakness accompanied by significant hypokalemia, hypomagnesemia and hypocalciuria in laboratory test with poor treatments. His mother had more slight symptoms of weakness than him with mild hypokalemia and hypocalciuria. Mild hypomagnesemia was also observed in his sister with occasional weakness. All other pedigree members had normal laboratory test with no GS-related symptoms. A homozygous mutation of SLC12A3 gene (c.488C > T) was detected by genetic testing in three members, and six were carriers of this mutation.

Conclusions

Genotype and phenotype vary significantly among GS patients. Male patients tend to experience more severe symptoms and poor treatment effect. Further large-scale population, animal, and molecular biology experiments are required to investigate the complexity of GS and to find a better treatment regimen for this disease.

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References

  1. Gitelman HJ, Graham JB, Welt LG (1966) A new familial disorder characterized by hypokalemia and hypomagnesemia. Trans Assoc Am Physicians 79:221–235

    CAS  PubMed  Google Scholar 

  2. Melander O, Orho-Melander M, Bengtsson K et al (2000) Genetic variants of thiazide-sensitive NaCl-cotransporter in Gitelman’s syndrome and primary hypertension. Hypertension 36:389–394

    Article  CAS  PubMed  Google Scholar 

  3. Mastroianni N, Bettinelli A, Bianchetti M et al (1996) Novel molecular variants of the Na-Cl cotransporter gene are responsible for Gitelman syndrome. Am J Hum Genet 59:1019–1026

    PubMed Central  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  5. Riveira-Munoz E, Chang Q, Bindels RJ, Devuyst O (2007) Gitelman’s syndrome: towards genotype-phenotype correlations? Pediatr Nephrol 22:326–332

    Article  PubMed  Google Scholar 

  6. Mastroianni N, De Fusco M, Zollo M et al (1996) Molecular cloning, expression pattern, and chromosomal localization of the human Na-Cl thiazide-sensitive cotransporter (SLC12A3). Genomics 35:486–493

    Article  CAS  PubMed  Google Scholar 

  7. Syrén ML, Tedeschi S, Cesareo L et al (2002) Identification of fifteen novel mutations in the SLC12A3 gene encoding the Na-Cl Co-transporter in Italian patients with Gitelman syndrome. Hum Mutat 20:78

    Article  PubMed  Google Scholar 

  8. Fu ACC, Lee KP, Tong LCT (2013) Gitelman’s Syndrome: Asymptomatic Hypokalaemia in a Chinese Boy. HK J Paediatr New Ser 18:174–177

    Google Scholar 

  9. Bettinelli A, Bianchetti MG, Borella P et al (1995) Genetic heterogeneity in tubular hypomagnesemia-hypokalemia with hypocalcuria (Gitelman’s syndrome). Kidney Int 47:547–551

    Article  CAS  PubMed  Google Scholar 

  10. Konrad M, Weber S (2003) Recent advances in molecular genetics of hereditary magnesium-losing disorders. J Am Soc Nephrol 14:249–260

    Article  PubMed  Google Scholar 

  11. Riveira-Munoz E, Chang Q, Godefroid N et al (2007) Belgian Network for Study of Gitelman Syndrome. Transcriptional and functional analyses of SLC12A3 mutations: new clues for the pathogenesis of Gitelman syndrome. J Am Soc Nephrol 18:1271–1283

    Article  CAS  PubMed  Google Scholar 

  12. Bouwer ST, Coto E, Santos F et al (2007) The Gitelman syndrome mutation, IVS9 + 1G > T, is common across Europe. Kidney Int 72:898

    Article  CAS  PubMed  Google Scholar 

  13. Tago N, Kokubo Y, Inamoto N et al (2004) A high prevalence of Gitelman’s syndrome mutations in Japanese. Hypertens Res 27:327–331

    Article  CAS  PubMed  Google Scholar 

  14. Luo J, Yang X, Liang J, Li W (2015) A pedigree analysis of two homozygous mutant Gitelman syndrome cases. Endocr J 62:29–36

    Article  CAS  PubMed  Google Scholar 

  15. Monnens L, Bindels R, Grünfeld JP (1998) Gitelman syndrome comes of age. Nephrol Dial Transplant 13:1617–1619

    Article  CAS  PubMed  Google Scholar 

  16. Shao L, Ren H, Wang W et al (2008) Novel SLC12A3 mutations in Chinese patients with Gitelman’s syndrome. Nephron Physiology 108:29–36

    Article  Google Scholar 

  17. Yasujima M, Tsutaya S (2009) Mutational analysis of a thiazide-sensitive Na-Cl cotransporter (SLC12A3) gene in a Japanese population-the Iwaki Health Promotion Project. Rinsho Byori 57:391–396

    CAS  PubMed  Google Scholar 

  18. Bouwer ST, Coto E, Santos F et al (2007) The Gitelman syndrome mutation, IVS9 + 1G > T, is common across Europe. Kidney Int 72:898

    Article  CAS  PubMed  Google Scholar 

  19. Riveira-Munoz E, Chang Q, Bindels RJ, Devuyst O (2007) Gitelman’s syndrome: towards genotype-phenotype correlations? Pediatr Nephrol 22:326–332

    Article  PubMed  Google Scholar 

  20. Li C, Zhou, Han W et a1 (2015) Identification of two novel mutations in SLC12A3 gene in two Chinese pedigrees with Gitelman Syndrome and review of literature. (Li C, et al., Clin Endocrinol Oxf). doi:10.1111/cen.12820

  21. Zhao Z, Pei Y, Huang X et al (2013) Novel TRPM6 mutations in familial hypomagnesemia with secondary hypocalcemia. Am J Nephrol 37:541–548

    Article  CAS  PubMed  Google Scholar 

  22. Graziani G, Fedeli C, Moroni L, Cosmai L, Badalamenti S, Ponticelli C (2010) Gitelman syndrome: pathophysiological and clinical aspects. QJM 103:741–748

    Article  CAS  PubMed  Google Scholar 

  23. Coto E, Rodriguez J, Jeck N et al (2004) A new mutation (intron 9 +1 G > T) in the SLC12A3 gene is linked to Gitelman syndrome in Gypsies. Kidney Int 65:25–29

    Article  CAS  PubMed  Google Scholar 

  24. Tseng MH, Yang SS, Hsu YJ et al (2012) Genotype, phenotype, and follow-up in Taiwanese patients with salt-losing tubulopathy associated with SLC12A3 mutation. J Clin Endocrinol Metab 97:E1478–E1482

    Article  CAS  PubMed  Google Scholar 

  25. Tago N, Kokubo Y, Inamoto N, Naraba H, Tomoike H, Iwai N (2004) A high prevalence of Gitelman’s syndrome mutations in Japanese. Hypertens Res 27:327–331

    Article  CAS  PubMed  Google Scholar 

  26. Balavoine AS, Bataille P, Vanhille P et al (2011) Phenotype-genotype correlation and follow-up in adult patients with hypokalaemia of renal origin suggesting Gitelman syndrome. Eur J Endocrinol 165:665–673

    Article  CAS  PubMed  Google Scholar 

  27. Enríquez R, Adam V, Sirvent AE et al (2010) Gitelman syndrome due to p. A204T mutation in CLCNKB gene. Int Urol Nephrol 42:1099–1102

    Article  PubMed  Google Scholar 

  28. Zelikovic I, Szargel R, Hawash A et al (2003) A novel mutation in the chloride channel gene, CLCNKB, as a cause of Gitelman and Bartter syndromes. Kidney Int 63:24–32

    Article  CAS  PubMed  Google Scholar 

  29. Riveira-Munoz E, Devuyst O, Belge H et al (2008) Evaluating PVALB as a candidate gene for SLC12A3-negative cases of Gitelman’s syndrome. Nephrol Dial Transplant 23:3120–3125

    Article  CAS  PubMed  Google Scholar 

  30. Lin SH, Cheng NL, Hsu YJ, Halperin ML (2004) Intrafamilial phenotype variability in patients with Gitelman syndrome having the same mutations in their thiazide-sensitive sodium/chloride cotransporter. Am J Kidney Dis 43:304–312

    Article  CAS  PubMed  Google Scholar 

  31. Lin SH, Shiang JC, Huang CC et al (2005) Phenotype and genotype analysis in Chinese patients with Gitelman’s syndrome. J Clin Endocrinol Metab 90:2500–2507

    Article  CAS  PubMed  Google Scholar 

  32. Chen Z, Vaughn DA, Fanestil DD (1994) Influence of gender on renal thiazide diuretic receptor density and response. J Am Soc Nephrol 5:1112–1119

    CAS  PubMed  Google Scholar 

  33. Verlander JW, Tran TM, Zhang L, Kaplan MR, Hebert SC (1998) Estradiol enhances thiazide-sensitive NaCl cotransporter density in the apical plasma membrane of the distal convoluted tubule in ovariectomized rats. J Clin Invest 101:1661–1669

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  34. Cruz DN, Shaer AJ, Bia MJ, Lifton RP, Simon DB (2001) Yale Gitelman’s and Bartter’s Syndrome Collaborative Study Group. Gitelman’s syndrome revisited: an evaluation of symptoms and health-related quality of life. Kidney Int 59:710–717

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

We express thanks to the Department of Laboratory Medicine, and Endocrinology and Metabolic Diseases Research room of West China Hospital, Sichuan University for laboratory test, DNA extraction and amplification. The authors also would like to thank the Joy Orient Translational Medicine Research Center for the work of Primer design and sequence analysis.

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Authors and Affiliations

  1. Department of Endocrinology and Metabolism, West China Hospital of Sichuan University, No. 37 Guoxue Lane, Chengdu, 610041, China

    Q. Lü, Y. Zhang, Z. An, L. Huang, L. Tang & N. Tong

  2. West China School of Medicine, Sichuan University, No.17, the 3rd section of the south of Renmin road, Chengdu, 610041, China

    C. Song, S. Wei & J. Huang

Authors
  1. Q. Lü
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  2. Y. Zhang
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  3. C. Song
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  4. Z. An
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  6. J. Huang
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  7. L. Huang
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  8. L. Tang
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  9. N. Tong
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Correspondence to N. Tong.

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The authors have no conflict of interest to declare.

Ethical approval

This article does not contain any studies with animals performed by any of the authors. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Informed consent was obtained from all individual participants included in the study.

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Lü, Q., Zhang, Y., Song, C. et al. A novel SLC12A3 gene homozygous mutation of Gitelman syndrome in an Asian pedigree and literature review. J Endocrinol Invest 39, 333–340 (2016). https://doi.org/10.1007/s40618-015-0371-y

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  • DOI: https://doi.org/10.1007/s40618-015-0371-y

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