Japanese Dent disease has a wider clinical spectrum than Dent disease in Europe/USA: genetic and clinical studies of 86 unrelated patients with low-molecular-weight proteinuria

Abstract

Dent disease is an X-linked disorder characterized by low-molecular-weight (LMW) proteinuria, hypercalciuria, nephrocalcinosis, urolithiasis and renal dysfunction. Dent disease is caused by mutations in at least two genes, i.e. CLCN5 and OCRL1, and its genetic background and phenotypes are common among European countries and the USA. However, only few studies on Dent disease in Japan, which was originally called 'low-molecular-weight proteinuric disease', have been reported thus far. In this study, we analysed genetic background and clinical phenotype and laboratory data of 86 unrelated Japanese Dent disease patients. The results demonstrated that the genetic basis of Japanese Dent disease was nearly identical to those of Dent disease in other countries. Of 86 unrelated Japanese Dent patients, 61 possessed mutations in CLCN5 (Dent-1), of which 27 were novel mutations; 11 showed mutations in OCRL1 (Dent-2), six of which were novel, and the remaining 14 patients showed no mutations in CLCN5 or OCRL1 (Dent-NI). Despite the similarity in genetic background, hypercalciuria was detected in only 51%, rickets in 2% and nephrocalcinosis in 35%. Although the patients were relatively young, six patients (8%) showed apparent renal dysfunction. Japanese Dent disease has a wider clinical spectrum than Dent disease in Europe and the USA.

Incidental Detection of Dent-2 Disease in an Infant with Febrile Proteinuria

“…The disease has great clinical variability from isolated low molecular weight proteinuria in Japanese patients to severe kidney disease with nephrocalcinosis, stones, and progression to end-stage renal disease [4]. Approximately 60% of patients have Dent-1 disease (OMIM300009), whereas 15% have mutations in OCRL1 (Dent-2 disease; OMIM300555).…”

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

“…Large insertions/deletions may be detected in around 4% of the patients. 6 OCRL mutations in Dent-2 disease patients are not uniformly distributed. Missense mutations are mainly found in exons 8-15, nonsense or frameshift mutations almost always affect exons 1-7.…”

“…[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.…”

“…Missense mutations are mainly found in exons 8-15, nonsense or frameshift mutations almost always affect exons 1-7. 6,7 Human wild-type ClC-5/OCRL-1 with their corresponding exon numbering are deposited in GenBank, accession nos. NG_007159.2 and NP_000267.2.…”

The ratio of urinary α1-microglobulin to microalbumin can be used as a diagnostic criterion for tubuloproteinuria

“…Low-molecular-weight proteinuria is one of the characteristic clinical manifestations of renal tubular and interstitial diseases, such as Dent disease, Lowe syndrome, acute tubulointerstitial nephritis (ATIN) without or with uveitis syndrome (TINU), Fanconi syndrome, and nephronophthisis (NPHP) (1,2). Lowmolecular-weight proteinuria is usually detected with urine protein electrophoresis (SDS polyacrylamide gel electrophoresis), but this technique is complicated and time-consuming.…”