Mutational Analysis of CLC-5, Cofilin and CLC-4 in Patients with Dent’s Disease

Abstract

Background/Aims: Dent’s disease is caused by mutations in the chloride/proton antiporter, CLC-5, or oculo-cerebro-renal-syndrome-of-Lowe (OCRL1) genes. Methods: Eighteen probands with Dent’s disease were investigated for mutations in CLC-5 and two of its interacting proteins, CLC-4 and cofilin. Wild-type and mutant CLC-5s were assessed in kidney cells. Urinary calcium excretion following an oral calcium challenge was studied in one family. Results: Seven different CLC-5 mutations consisting of two nonsense mutations (Arg347Stop and Arg718Stop), two missense mutations (Ser244Leu and Arg516Trp), one intron 3 donor splice site mutation, one deletion-insertion (nt930delTCinsA) and an in-frame deletion (523delVal) were identified in 8 patients. In the remaining 10 patients, DNA sequence abnormalities were not detected in the coding regions of CLC-4 or cofilin, and were independently excluded for OCRL1. Patients with CLC-5 mutations were phenotypically similar to those without. The donor splice site CLC-5 mutation resulted in exon 3 skipping. Electrophysiology demonstrated that the 523delVal CLC-5 mutation abolished CLC-5-mediated chloride conductance. Sixty percent of women with the CLC-5 deletion-insertion had nephrolithiasis, although calcium excretion before and after oral calcium challenge was similar to that in unaffected females. Conclusions: Three novel CLC-5 mutations were identified, and mutations in OCRL1, CLC-4 and cofilin excluded in causing Dent’s disease in this patient cohort.

Dent disease: Same <i>CLCN5</i> mutation but different phenotypes in two brothers in China

“…Table 3. Laboratory data of the two brothers as Fanconi syndrome (20,21). Our two brothers have the same mutation but presented a different phenotype, one Dent disease while the other Fanconi syndrome.…”

“…No variations were found in inherited Fanconi syndrome related genes in both cases, such as OCRL1, COQ2, CNTS, GALT1, ALDOB, SLC2A2, SLC5A2, ATP7B, or NDUFAF6. The mutation has been reported (20,21).…”

“…The prevalence of Dent disease is unknown and it may be underdiagnosed. Dent disease mainly affects males, whereas female carriers may show a milder phenotype (5,6). Patients are usually diagnosed in childhood or in young adult years.…”

Clinical utility gene card for: Dent disease (Dent-1 and Dent-2)

“…[1][2][3][4][5][6] The mutational spectrum includes missense (44%) and nonsense (26%) mutations, small deletions/insertions (15%) and splice defects (11%), with a few hotspots, mainly affecting arginine codons. Large insertions/deletions may be detected in around 4% of the patients.…”

Dent's disease complicated by nephrotic syndrome: A case report

“…Dent's disease is divided into two types depending on the phenotype: Dent's disease 1 (OMIM #300009), which is caused by mutations in the CLCN5 gene located on chromosome Xp 11.22, and Dent's disease 2 (OMIM#300555), which is caused by mutations in the OCRL gene located on chromosome Xq25 (3). Dent's disease mainly affects males, whereas female carriers may display a milder phenotype (4,5). Patients are usually diagnosed in childhood or in their early adult years.…”