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J Pediatr Genet 2019; 08(04): 235-239
DOI: 10.1055/s-0039-1692172
Case Report
Georg Thieme Verlag KG Stuttgart · New York

A Novel CLCN5 Splice Site Mutation in a Boy with Incomplete Phenotype of Dent Disease

Maria Bitsori
1   Department of Paediatrics, Heraklion University Hospital, Crete, Greece
,
Eleni Vergadi 
2   Department of Paediatrics, School of Medicine, University of Crete, Heraklion, Crete, Greece
,
Emmanouil Galanakis
2   Department of Paediatrics, School of Medicine, University of Crete, Heraklion, Crete, Greece
› Author Affiliations
Further Information

Publication History

17 February 2019

22 April 2019

Publication Date:
04 June 2019 (online)

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Abstract

Dent disease is a rare X-linked renal proximal tubulopathy presenting with low-molecular-weight proteinuria (LMWP), hypercalciuria, and nephrocalcinosis, other signs of incomplete renal Fanconi syndrome, and renal failure. Early identification of patients who harbor disease-associated mutations is important for effective medical care and avoidance of unnecessary interventions. We report the case of an asymptomatic 9-year-old boy who presented with proteinuria in routine examination. Further investigation revealed the presence of nephrotic range proteinuria, mostly LMWP and mild hypercalciuria without nephrocalcinosis, or other features of tubular dysfunction. Renal function, growth, and bone mineral density were within regular limits. The male gender and the presence of LMWP and hypercalciuria even in the absence of other findings prompted us to genetic investigation for Dent disease. A novel splice site mutation (c.416–2A > G) of the chloride voltage-gated channel 5 (CLCN5) gene, responsible for Dent disease type 1 was identified. In silico analysis revealed that this mutation interferes with the mating of exons 4 and 5. Due to early molecular diagnosis, our patient did not undergo a renal biopsy, neither required aggressive pharmacological interventions. This case underscores the diversity and complexity of CLCN5 mutations and highlights the importance of early molecular testing in male patients with incomplete phenotype of Dent disease.

Keywords

Dent disease - CLCN5 mutation - proteinuria - hypercalciuria

Note

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


Ethical Approval

Ethical approval was not applicable in our case.


 

  • References

  • 1 Dent CE, Friedman M. Hypercalcuric rickets associated with renal tubular damage. Arch Dis Child 1964; 39: 240-249
    CrossrefPubMedGoogle Scholar
  • 2 Devuyst O, Thakker RV. Dent's disease. Orphanet J Rare Dis 2010; 5: 28
    CrossrefPubMedGoogle Scholar
  • 3 Mansour-Hendili L, Blanchard A, Le Pottier N. , et al. Mutation update of the CLCN5 gene responsible for Dent disease 1. Hum Mutat 2015; 36 (08) 743-752
    CrossrefPubMedGoogle Scholar
  • 4 Ludwig M, Waldegger S, Nuutinen M. , et al. Four additional CLCN5 exons encode a widely expressed novel long CLC-5 isoform but fail to explain Dent's phenotype in patients without mutations in the short variant. Kidney Blood Press Res 2003; 26 (03) 176-184
    CrossrefPubMedGoogle Scholar
  • 5 Tang X, Brown MR, Cogal AG. , et al. Functional and transport analyses of CLCN5 genetic changes identified in Dent disease patients. Physiol Rep 2016; 4 (08) e12776
    CrossrefPubMedGoogle Scholar
  • 6 van Berkel Y, Ludwig M, van Wijk JAE, Bökenkamp A. Proteinuria in Dent disease: a review of the literature. Pediatr Nephrol 2017; 32 (10) 1851-1859
    CrossrefPubMedGoogle Scholar
  • 7 Günther W, Piwon N, Jentsch TJ. The ClC-5 chloride channel knock-out mouse - an animal model for Dent's disease. Pflugers Arch 2003; 445 (04) 456-462
    CrossrefPubMedGoogle Scholar
  • 8 Ludwig M, Utsch B, Balluch B, Fründ S, Kuwertz-Bröking E, Bökenkamp A. Hypercalciuria in patients with CLCN5 mutations. Pediatr Nephrol 2006; 21 (09) 1241-1250
    CrossrefPubMedGoogle Scholar
  • 9 Kodner C. Nephrotic syndrome in adults: diagnosis and management. Am Fam Physician 2009; 80 (10) 1129-1134
    PubMedGoogle Scholar
  • 10 Desmet FO, Hamroun D, Lalande M, Collod-Béroud G, Claustres M, Béroud C. Human splicing finder: an online bioinformatics tool to predict splicing signals. Nucleic Acids Res 2009; 37 (09) e67
    CrossrefPubMedGoogle Scholar
  • 11 Yeo G, Burge CB. Maximum entropy modeling of short sequence motifs with applications to RNA splicing signals. J Comput Biol 2004; 11 (2-3): 377-394
    CrossrefPubMedGoogle Scholar
  • 12 Ludwig M, Utsch B, Monnens LA. Recent advances in understanding the clinical and genetic heterogeneity of Dent's disease. Nephrol Dial Transplant 2006; 21 (10) 2708-2717
    CrossrefPubMedGoogle Scholar
  • 13 Blanchard A, Curis E, Guyon-Roger T. , et al. Observations of a large Dent disease cohort. Kidney Int 2016; 90 (02) 430-439
    CrossrefPubMedGoogle Scholar
  • 14 Cramer MT, Charlton JR, Fogo AB, Fathallah-Shaykh SA, Askenazi DJ, Guay-Woodford LM. Expanding the phenotype of proteinuria in Dent disease. A case series. Pediatr Nephrol 2014; 29 (10) 2051-2054
    CrossrefPubMedGoogle Scholar
  • 15 Frishberg Y, Dinour D, Belostotsky R. , et al. Dent's disease manifesting as focal glomerulosclerosis: is it the tip of the iceberg?. Pediatr Nephrol 2009; 24 (12) 2369-2373
    CrossrefPubMedGoogle Scholar
  • 16 Solanki AK, Arif E, Morinelli T. , et al. A novel CLCN5 mutation associated with focal segmental glomerulosclerosis and podocyte injury. Kidney Int Rep 2018; 3 (06) 1443-1453
    PubMedGoogle Scholar
  • 17 De Mutiis C, Pasini A, La Scola C, Pugliese F, Montini G. Nephrotic-range albuminuria as the presenting symptom of Dent-2 disease. Ital J Pediatr 2015; 41: 46
    CrossrefPubMedGoogle Scholar
  • 18 Li F, Yue Z, Xu T. , et al. Dent disease in Chinese children and findings from heterozygous mothers: phenotypic heterogeneity, fetal growth, and 10 novel mutations. J Pediatr 2016; 174: 204-210.e1
    CrossrefPubMedGoogle Scholar
  • 19 Carballo-Trujillo I, Garcia-Nieto V, Moya-Angeler FJ. , et al. Novel truncating mutations in the ClC-5 chloride channel gene in patients with Dent's disease. Nephrol Dial Transplant 2003; 18 (04) 717-723
    CrossrefPubMedGoogle Scholar
  • 20 Wong W, Poke G, Stack M, Kara T, Prestidge C, Flintoff K. Phenotypic variability of Dent disease in a large New Zealand kindred. Pediatr Nephrol 2017; 32 (02) 365-369
    CrossrefPubMedGoogle Scholar
  • 21 Vezzoli G, Corghi E, Edefonti A. , et al. Nonacidotic kidney proximal tubulopathy with absorptive hypercalciuria. Am J Kidney Dis 1995; 25 (02) 222-227
    CrossrefPubMedGoogle Scholar
  • 22 Anglani F, D'Angelo A, Bertizzolo LM. , et al; Dent Disease Italian Network. Nephrolithiasis, kidney failure and bone disorders in Dent disease patients with and without CLCN5 mutations. Springerplus 2015; 4: 492
    CrossrefPubMedGoogle Scholar
  • 23 Lewandowska MA. The missing puzzle piece: splicing mutations. Int J Clin Exp Pathol 2013; 6 (12) 2675-2682
    PubMedGoogle Scholar
  • 24 Caminsky N, Mucaki EJ, Rogan PK. Interpretation of mRNA splicing mutations in genetic disease: review of the literature and guidelines for information-theoretical analysis. F1000 Res 2014; 3: 282
    CrossrefPubMedGoogle Scholar
  • 25 Baralle D, Lucassen A, Buratti E. Missed threads. The impact of pre-mRNA splicing defects on clinical practice. EMBO Rep 2009; 10 (08) 810-816
    PubMedGoogle Scholar
  • 26 Perdomo-Ramirez A, de Armas-Ortiz M, Ramos-Trujillo E, Suarez-Artiles L, Claverie-Martin F. Exonic CLDN16 mutations associated with familial hypomagnesemia with hypercalciuria and nephrocalcinosis can induce deleterious mRNA alterations. BMC Med Genet 2019; 20 (01) 6
    PubMedGoogle Scholar
  • 27 Suarez-Artiles L, Perdomo-Ramirez A, Ramos-Trujillo E, Claverie-Martin F. Splicing analysis of exonic OCRL mutations causing Lowe syndrome or Dent-2 disease. Genes (Basel) 2018; 9 (01) E15
    CrossrefPubMedGoogle Scholar
  • 28 Valina MR, Larsen CP, Kanosky S, Suchy SF, Nield LS, Onder AM. A novel CLCN5 mutation in a boy with asymptomatic proteinuria and focal global glomerulosclerosis. Clin Nephrol 2013; 80 (05) 377-384
    CrossrefPubMedGoogle Scholar