Dent's disease: Identification of seven new pathogenic mutations in the CLCN5 gene.
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.
Research Unit, Nuestra Señora de Candelaria Hospital, Santa Cruz de Tenerife, Spain.
Elena
E
Ramos-Trujillo
Research Unit, Nuestra Señora de Candelaria Hospital, Santa Cruz de Tenerife, Spain.
Felix
F
Claverie-Martin
Department of Pediatric Nephrology, Nuestra Señora de Candelaria Hospital, Santa Cruz de Tenerife, Spain.
Victor
V
Garcia-Nieto
Department of Pediatric Nephrology, Vall d'Hebron Hospital, Barcelona, Spain.
Gema
G
Ariceta
Department of Pediatric Nephrology, 12 de Octubre Hospital, Madrid, Spain.
Julia
J
Vara
Research Unit, Nuestra Señora de Candelaria Hospital, Santa Cruz de Tenerife, Spain.
Hilaria
H
Gonzalez-Acosta
Department of Pediatric Nephrology, Maternal and Infantile Hospital, Malaga, Spain.
Marta
M
Garcia-Ramirez
Pediatric Nephrology, Clinical Hospital, Valencia, Spain.
Jaime
J
Fons
Research Unit, Nuestra Señora de Candelaria Hospital, Santa Cruz de Tenerife, Spain.
Elizabeth
E
Cordoba-Lanus
Research Unit, Nuestra Señora de Candelaria Hospital, Santa Cruz de Tenerife, Spain.
Javier
J
Gonzalez-Paredes
Department of Pediatric Nephrology, Insular-Materno Infantil Hospital, Las Palmas de Gran Canaria, Spain.
Blanca
B
Valenciano
Department of Pediatric Nephrology, Insular-Materno Infantil Hospital, Las Palmas de Gran Canaria, Spain.
Leticia
L
Ramos
Department of Pediatric Nephrology, 12 de Octubre Hospital, Madrid, Spain.
Rafael
R
Muley
Department of Nephrology, Pereira Rossell Hospital, Medical School, Montevideo, Uruguay.
Marina
M
Caggiani
Department of Pediatric Nephrology, University Hospital, Guadalajara, Spain.
Pilar
P
Alvarez-Estrada
Department of Pediatric Nephrology, Vall d'Hebron Hospital, Barcelona, Spain.
Alvaro
A
Madrid
Hereditary tubular disorders; hypercalciuria; low-molecular-weight proteinuria; mutation analysis; nephrocalcinosis; nephrolithiasis