Dent’s disease: Identification of seven new pathogenic mutations in the CLCN5 gene

Article type: Research Article

Authors: Ramos-Trujillo, Elena | Claverie-Martin, Felix^; | Garcia-Nieto, Victor | Ariceta, Gema | Vara, Julia | Gonzalez-Acosta, Hilaria | Garcia-Ramirez, Marta | Fons, Jaime | Cordoba-Lanus, Elizabeth | Gonzalez-Paredes, Javier | Valenciano, Blanca | Ramos, Leticia | Muley, Rafael | Caggiani, Marina | Alvarez-Estrada, Pilar | Madrid, Alvaro | for the RenalTube Group

Affiliations: Research Unit, Nuestra Señora de Candelaria Hospital, Santa Cruz de Tenerife, Spain | Department of Pediatric Nephrology, Nuestra Señora de Candelaria Hospital, Santa Cruz de Tenerife, Spain | Department of Pediatric Nephrology, Vall d’Hebron Hospital, Barcelona, Spain | Department of Pediatric Nephrology, 12 de Octubre Hospital, Madrid, Spain | Department of Pediatric Nephrology, Maternal and Infantile Hospital, Malaga, Spain | Pediatric Nephrology, Clinical Hospital, Valencia, Spain | Department of Pediatric Nephrology, Insular-Materno Infantil Hospital, Las Palmas de Gran Canaria, Spain | Department of Nephrology, Pereira Rossell Hospital, Medical School, Montevideo,Uruguay | Department of Pediatric Nephrology, University Hospital, Guadalajara, Spain

Note: [] Corresponding author: Felix Claverie-Martin, Unidad de Investigacion, Hospital Nuestra Señora de Candelaria, 38010 Santa Cruz de Tenerife, Spain. Tel.: +34 922 600 546; Fax: +34 922 600 562; E-mail: [email protected].

Abstract: Dent’s disease is an X-linked proximal tubulopathy characterized by low-molecular-weight proteinuria, hypercalciuria, nephrocalcinosis, nephrolithiasis and progressive renal failure. This disorder is frequently caused by mutations in the CLCN5 gene encoding the electrogenic chloride/proton exchanger ClC-5. Occasionally, Dent’s disease has been associated to atypical cases of asymptomatic proteinuria with focal glomerulosclerosis. Twelve unrelated patients with Dent’s disease, including two who presented with asymptomatic proteinuria and developed glomerulosclerosis, were studied. Mutational analysis of the CLCN5 gene was performed by DNA sequencing. We identified thirteen distinct CLCN5 mutations in the twelve patients. Seven of these mutations, p.P416fsX*17, p.[H107P, V108fs*27], p.G466D, p.G65R, p.G462S, p.Y164* and c.723+1G >T, were novel and possibly pathogenic. In one family, the patient’s mother was not a carrier of the respective mutation. Our results increased the spectrum of CLCN5 disease causing defects with seven new pathogenic mutations and established a de novo origin in one of them. Remarkably, three new missense mutations, p.G466D, p.G65R and p.G462S, affect highly conserved glycine residues located in transmembrane α-helix GxxxG packing motifs. The two atypical cases further support that the diagnosis of Dent’s disease should be considered in children with asymptomatic proteinuria and focal glomerulosclerosis and without evidence of primary glomerular disease.

Keywords: Hereditary tubular disorders, mutation analysis, low-molecular-weight proteinuria, hypercalciuria, nephrocalcinosis, nephrolithiasis

DOI: 10.3233/PGE-13061

Journal: Journal of Pediatric Genetics, vol. 2, no. 3, pp. 133-140, 2013