RARE DISEASE
Dent disease type 1
Dent disease type 1
Dent disease type 1
Drug discovery
23
papers
On emerging therapies
Overview
Dent disease type 1 is an X-linked recessive renal tubulopathy caused by inactivating mutations in the CLCN5 gene. It primarily affects proximal tubule function, manifesting as low-molecular-weight proteinuria (100% of cases), hypercalciuria (90-95%), nephrocalcinosis/nephrolithiasis (30-50%), and progressive CKD, often progressing to end-stage renal failure by the third to fifth decade [1][2][5]. Extrarenal manifestations are absent, distinguishing it from Dent type 2 [1][3].
Burden
35-75% develop ESRD by age 50-60, with annual eGFR decline ~1.1 mL/min/1.73m² [4][5].
Morbidity driven by recurrent nephrolithiasis (30-50%), growth impairment, and bone deformities [2][5][13].
Economic burden includes lifelong nephrology care, dialysis/transplant costs, and genetic testing [1][10].
Therapies
Supportive care: Thiazide diuretics (limited efficacy, risk of hypokalemia), potassium citrate for nephrolithiasis, and ACE/ARB therapy for proteinuria [1][4][10].
Avoid vitamin D unless severe rickets develops due to risk of exacerbating hypercalciuria [4][10].
Genetic counseling for X-linked inheritance; kidney transplantation remains definitive treatment for ESRD [1][5].
Categories: rare bone diseases, rare developmental anomalies during embryogenesis, rare endocrine diseases, rare genetic diseases, rare renal diseases, rare transplant-related disorders
Research Papers
23 drug discovery papers about Dent disease type 1, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
23 drug discovery papers about Dent disease type 1, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
proteins
2026-04-01 | Use of recombinant growth hormone in the treatment of short stature in a sibling pair with Dent disease
ABSTRACT Dent disease (DD) is a rare X-linked recessive proximal tubulopathy characterized by low molecular-weight proteinuria, nephrolithiasis, and slowly progressive renal failure. It is caused by mutations in the chloride channel chloride voltage-gated channel 5 (CLCN5) or the oculocerebrorenal syndrome of Lowe gene. We describe two brothers with genetically confirmed DD type 1 due to a pathogenic CLCN5 duplication (c.351_352dupAA). The elder sibling, diagnosed 9 years after presenting with frothy urine, developed progressive growth retardation despite conventional therapy. At 15 years, his height was −3.5 standard deviation (SD) with a normal growth hormone (GH)–insulin-like growth factor-1 (IGF-1) axis. His younger brother, identified on family screening, had severe short stature (−4.1 SD) and documented GH deficiency on clonidine stimulation. After informed consent from parents, both received recombinant GH (rGH, 0.18 mg/kg/week) in addition to standard management for 1 year. They showed significant height gain without any complications of rGH therapy. Serum phosphate and tubular phosphate reabsorption improved, while renal function and calciuria remained stable. To conclude, short stature in DD is multifactorial, and GH deficiency may be one of the contributing factors. Conventional treatment often fails to address the issue of short stature in these patients. Treatment with rGH demonstrated improved growth velocity and suggests potential therapeutic benefits in these patients regardless of GH–IGF-1 axis function.
2024-07-18 | A novel transgenic mouse model highlights molecular disruptions involved in the pathogenesis of Dent disease 1.
Dent disease (DD) is a hereditary renal disorder characterized by low molecular weight (LMW) proteinuria and progressive renal failure. Inactivating mutations of the CLCN5 gene encoding the 2Cl-/H+exchanger ClC-5 have been identified in patients with DD type 1. ClC-5 is essentially expressed in proximal tubules (PT) where it is thought to play a role in maintaining an efficient endocytosis of LMW proteins. However, the exact pathological roles of ClC-5 in progressive dysfunctions observed in DD type 1 are still unclear. To address this issue, we designed a mouse model carrying the most representative type of ClC-5 missense mutations found in DD patients. These mice showed a characteristic DD type 1 phenotype accompanied by altered endo-lysosomal system and autophagy functions. With ageing, KI mice showed increased renal fibrosis, apoptosis and major changes in cell metabolic functions as already suggested in previous DD models. Furthermore, we made the interesting new discovery that the Lipocalin-2-24p3R pathway might be involved in the progression of the disease. These results suggest a crosstalk between the proximal and distal nephron in the pathogenesis mechanisms involved in DD with an initial PT impairment followed by the Lipocalin-2 internalisation and 24p3R overexpression in more distal segments of the nephron. This first animal model of DD carrying a pathogenic mutation of Clcn5 and our findings pave the way aimed at exploring therapeutic strategies to limit the consequences of ClC-5 disruption in patients with DD type 1 developing chronic kidney disease.
2018-12-24 | OCRL deficiency impairs endolysosomal function in a humanized mouse model for Lowe syndrome and Dent disease
Mutations in OCRL encoding the inositol polyphosphate 5-phosphatase OCRL (Lowe oculocerebrorenal syndrome protein) disrupt phosphoinositide homeostasis along the endolysosomal pathway causing dysfunction of the cells lining the kidney proximal tubule (PT). The dysfunction can be isolated (Dent disease 2) or associated with congenital cataracts, central hypotonia and intellectual disability (Lowe syndrome). The mechanistic understanding of Dent disease 2/Lowe syndrome remains scarce due to limitations of animal models of OCRL deficiency. Here, we investigate the role of OCRL in Dent disease 2/Lowe syndrome by using OcrlY/− mice, where the lethal deletion of the paralogue Inpp5b was rescued by human INPP5B insertion, and primary culture of proximal tubule cells (mPTCs) derived from OcrlY/− kidneys. The OcrlY/− mice show muscular defects with dysfunctional locomotricity and present massive urinary losses of low-molecular-weight proteins and albumin, caused by selective impairment of receptor-mediated endocytosis in PT cells. The latter was due to accumulation of phosphatidylinositol 4,5–bisphosphate PI(4,5)P2 in endolysosomes, driving local hyper-polymerization of F-actin and impairing trafficking of the endocytic LRP2 receptor, as evidenced in OcrlY/− mPTCs. The OCRL deficiency was also associated with a disruption of the lysosomal dynamic and proteolytic activity. Partial convergence of disease-pathways and renal phenotypes observed in OcrlY/− and Clcn5Y/− mice suggest shared mechanisms in Dent diseases 1 and 2. These studies substantiate the first mouse model of Lowe syndrome and give insights into the role of OCRL in cellular trafficking of multiligand receptors. These insights open new avenues for therapeutic interventions in Lowe syndrome and Dent disease.
2004-01-23 | Coexpression of complementary fragments of ClC-5 and restoration of chloride channel function in a Dent's disease mutation.
The human hereditary disorder Dent's disease is linked to loss-of-function mutations of the chloride channel ClC-5. Many of these mutations involve insertion of premature stop codons, resulting in truncation of the protein. We determined whether the functional activity of ClC-5 could be restored by coexpression of the truncated protein (containing the NH2-terminal region) with its complementary "missing" COOH-terminal region. Split channel constructs for ClC-5, consisting of complementary N and C protein regions, were created at an arbitrary site in the COOH-terminal region (V655) and at four Dent's disease mutation sites (R347, Y617, R648, and R704). Coexpression of complementary fragments for the split channel at V655 produced currents with anion and pH sensitivity similar to those of wild-type ClC-5. Channel activity was similarly restored when complementary split channel constructs made for Dent's mutation R648 were coexpressed, but no ClC-5 currents were found when split channels for mutations R347, Y617, or R704 were coexpressed. Immunoblot and immunofluorescence studies of COS-7 cells revealed that N or C protein fragments could be transiently expressed and detected in the plasma membrane, even in split channels that failed to show functional activity. The results suggest that ClC-5 channel activity can be restored for specific Dent's mutations by expression of the missing portion of the ClC-5 molecule.
small molecules
2026-07-07 | The Missense Mutant ClC-5 (E211A), associated with Proton/Chloride Uncoupling Exacerbates Renal Pathology Compared to the ClC-5 null Mutant.
Dent disease type 1 is an X-linked proximal tubulopathy caused by mutations in CLCN5, which encodes the chloride/proton exchanger ClC-5. While loss-of-function mutations impair endocytosis and lead to progressive renal disease, the pathological consequences of uncoupling mutations that selectively disrupt Cl-/H+ exchange remain incompletely understood. In this study, we examined the renal phenotype associated with the ClC-5 E211A uncoupling mutation, which abolishes proton transport while preserving chloride conductance, and compared it with that of ClC-5 null mice. Contrary to the expectation that partial transport activity would mitigate disease severity, E211A mutant mice developed more severe and progressive kidney pathology than null mutants. Both models exhibited early low-molecular-weight proteinuria, including marked urinary excretion of β2-microglobulin and vitamin D-binding protein. However, E211A mutants displayed progressive polyuria, reduced body weight, and pronounced interstitial fibrosis at 5 and 18 months of age, changes not observed in ClC-5 null mice. Renal injury in E211A mutants was characterized by glomerular abnormalities, including enlarged Bowman's spaces, cyst formation, reduced podocyte markers Wilms tumor protein and nephrin, and age-dependent tubular degeneration. ClC-5 E211A protein showed altered localization and reduced expression in vivo, suggesting disrupted trafficking or stability. Phenotypic severity was strongly influenced by genetic background, underscoring its modulatory role in disease expression. Together, these findings demonstrate that the ClC-5 E211A uncoupling mutation induces additional adverse effects that exceed those caused by complete loss of ClC-5. Our results reveal that uncoupling mutations can drive progressive kidney damage through mechanisms distinct from gene knockout and highlight the need for mutation-specific therapeutic strategies for Dent disease type 1.
2026-02-27 | The Significance of Fibroblast Growth Factor 23 and 24,25-Dihydroxyvitamin D in Dent Disease Type 1.
Fibroblast growth factor 23 and 24,25-dihydroxyvitamin D are positively correlated and are significantly lower in Dent disease than in idiopathic calcium kidney stones patients. Dent patients with low 24,25-dihydroxyvitamin D had greater hypercalciuria and proteinuria, and, among adults, higher 1,25-dihydroxyvitamin D concentrations. Moderate phosphate supplementation mitigates hypercalciuria. Hypercalciuria is a prominent characteristic in Dent disease type 1 (DD1) and is associated with kidney stones and nephrocalcinosis. The objectives of this study were to assess fibroblast growth factor 23 (FGF23) and 24,25-dihydroxyvitamin D (24,25(OH) 2 D) in DD1 patients and investigate the effects of phosphate supplementation on urinary calcium excretion. Serum and 24-hour urine assessments from adult and pediatric DD1 patients ( N =10 adults; N =9 pediatrics) were compared with adult control subjects with a history of idiopathic calcium kidney stones and hypercalciuria ( N =9). Adult DD1 patients and control participants completed an oral phosphate supplementation intervention (1 g/d×14 days) with reassessment immediately after intervention. FGF23 was significantly lower in DD1 than in the control cohort (adults, P = 0.006) and positively correlated with 24,25(OH) 2 D across all study cohorts. The concentrations of 24,25(OH) 2 D were low with conversion ratios (25-hydroxyvitamin D: 24,25(OH) 2 D) exceeding the clinical reference limit for five of 10 adults and six of 9 pediatric DD1 patients. The DD1 cohorts were then stratified by the 24,25(OH) 2 D ratio into "normal" and "low" 24,25(OH) 2 D. Adult DD1 patients with low 24,25(OH) 2 D ( n =5) had lower FGF23, higher 1,25-dihydroxyvitamin D, greater urine calcium, and greater urine protein. Pediatric stratified data mirrored that in adults with the exception of no difference in serum 1,25-dihydroxyvitamin D. Phosphate supplementation was effective in decreasing urine calcium in both adult DD1 and control adult cohorts. Clinical measurement of 24,25(OH) 2 D is a novel and useful analysis for evaluating the severity of calcium and protein dysregulation in DD1. In addition, moderate phosphate supplementation effectively mitigates urine calcium excretion in DD1 adult patients. ClinicalTrials.gov, NCT02016235 .
2025-10-01 | Native Kidney Embolization as Minimally Invasive Treatment for Post-Transplant Polyuria
Introduction: High native kidney urine output post-transplant can lead to dehydration, poor graft perfusion, and increased risk of acute kidney injuries. We describe native kidney embolization as an effective, less invasive, lower morbidity alternative to nephrectomy for patients with post-transplant polyuria. Case Description: Seven patients ages 4 to 19 with renal disease from Bardet-Biedl syndrome, Dent disease, primary hyperoxaluria type 1, renal cortical necrosis, and obstructive uropathy underwent post-transplant native kidney embolization for high urine output. Barriers to performing nephrectomy included horseshoe kidney, elevated BMI, surgical history, and behavioral concerns. Interventional Radiology performed all embolizations via a femoral approach. Angiogram was performed to assess anatomy, followed by ethanol and coil embolization, with repeat angiogram after to ensure success. All patients received a short steroid taper for prevention of post-embolization syndrome. Hospital length of stay was 4-8 days post-embolization. Three patients required ICU stay for sedation during lay flat time post-procedure. Pain was overall well-controlled. Six of seven had lower 24-hour fluid intake requirements post-embolization, with subjective reports of 50-75% decrease in urine output from one patient, and decrease in overnight diapers from another. Half had improvement in GFR post-procedure. Patients with prior hospitalizations for acute kidney injury from dehydration had a decrease in these episodes post-embolization. One patient with primary hyperoxaluria had continued decline in plasma oxalate levels post-embolization. Discussion: This case series demonstrates that native kidney embolization was successful and well tolerated. Pain was well-controlled, with no significant complications from the procedure. Half of the patients experienced improved GFR, and multiple patients reported subjective decrease in urine output after the procedure. Native kidney embolization can be considered an effective, less invasive and lower morbidity alternative to nephrectomy for patients with post-transplant polyuria.
2024-08-28 | [Two cases of Dent disease type 1 with Bartter-like phenotype and literature review].
The clinical presentation, treatment, and follow-up of two boys with type 1 Dent disease who exhibited a Bartter-like phenotype were retropectively analysed. The related literature of pediatric patients with type 1 Dent disease who had hypokalemia and metabolic alkalosis was screened through databases such as PubMed, CNKI, and Wanfang until February 1, 2024, and common features among these patients were summarized through literature review. A total of 7 literatures were included, and 9 children were included in the analysis. All patients were male, presenting with significant low molecular weight proteinuria and hypercalciuria. Other prominent characteristic phenotypes included short stature (7/8), hypophosphatemia (8/9), and rickets (6/8). Seven previously reported patients had missense or nonsense mutations, while 2 patients in this study carried possible pathogenic mutations in the CLCN5 gene, c.315+2T>A (p.?) and c.584dupT (p.I196Yfs*6), respectively. Five patients were able to maintain blood potassium levels around 3 mmol/L with oral potassium chloride solution combined with non-steroidal anti-inflammatory drugs (ibuprofen or indomethacin). The follow-up showed that 2 patients developed chronic kidney disease stage 4 and stage 3 at the age of 13 and 21 years, respectively. The phenotypic overlap between Dent disease and Batter syndrome is considerable,with the distinguishing feature being the presence of significant low molecular weight proteinuria. Patients with type 1 Dent disease presenting with the Bartter-like phenotype have a high prevalence of short stature, hypophosphatemia, and rickets. Non-steroidal anti-inflammatory drugs can be used to correct hypokalemia in patients under periodic renal function assessment. 回顾性分析2例以巴特样表型起病的登特病1型男性患儿的临床表现、治疗及随访。检索PubMed、知网、万方等数据库，从建库至2024年2月1日，筛选低钾血症合并代谢性碱中毒的登特病1型患儿相关文献，通过文献复习总结此病患儿的临床特征。纳入7篇文献，9例患儿纳入分析。患者均为男性，均有大量低分子蛋白尿和高钙尿症，其他突出的特征性表型包括身材矮小（7/8）、低磷血症（8/9）及佝偻病（6/8）。已报道的7例患者为CLCN5基因错义或无义突变，本研究报道的2例患者分别携带CLCN5基因可能致病性突变：c.315+2T>A（p.？）及c.584dupT（p.I196Yfs*6）。5例患者经氯化钾口服液联合非甾体类抗炎药（布洛芬或吲哚美辛）能维持血钾水平在3 mmol/L左右。随访显示有2例患者分别在13和21岁时出现慢性肾脏病4期和3期。登特病与巴特综合征表型重合度高，鉴别点在于是否存在大量低分子蛋白尿。以巴特样表型起病的登特病1型患者身材矮小、低磷血症及佝偻病的发生率高。在定期检测肾功能的情况下，非甾体抗炎药可用于纠正患者的低钾血症。.
2024-08-10 | 4-Phenylbutyric Acid Treatment Reduces Low-Molecular-Weight Proteinuria in a Clcn5 Knock-in Mouse Model for Dent Disease-1.
Dent disease-1 (DD-1) is a rare X-linked tubular disorder characterized by low-molecular-weight proteinuria (LMWP), hypercalciuria, nephrolithiasis and nephrocalcinosis. This disease is caused by inactivating mutations in the CLCN5 gene which encodes the voltage-gated ClC-5 chloride/proton antiporter. Currently, the treatment of DD-1 is only supportive and focused on delaying the progression of the disease. Here, we generated and characterized a Clcn5 knock-in mouse model that carries a pathogenic CLCN5 variant, c. 1566_1568delTGT; p.Val523del, which has been previously detected in several DD-1 unrelated patients, and presents the main clinical manifestations of DD-1 such as high levels of urinary b2-microglobulin, phosphate and calcium. Mutation p.Val523del causes partial ClC-5 retention in the endoplasmic reticulum. Additionally, we assessed the ability of sodium 4-phenylbutyrate, a small chemical chaperone, to ameliorate DD-1 symptoms in this mouse model. The proposed model would be of significant value in the investigation of the fundamental pathological processes underlying DD-1 and in the development of effective therapeutic strategies for this rare condition.
cell therapies
2023-09-08 | Generation of a human induced pluripotent stem cell line from a patient with dent disease.
Dent disease, an X-linked tubular disorder, is a rare condition that leads to low-molecular-weight proteinuria, hypercalciuria, kidney stones, and chronic kidney disease. Here, we successfully established a human induced pluripotent stem cells (hiPSC) line from peripheral blood mononuclear cells of 10-year-old male with Dent disease 1 caused by the mutation of Chloride Voltage-Gated Channel 5 gene. This hiPSCs displayed features similar to human embryonic stem cells, including pluripotency-associated markers expression, normal karyotype, and the ability to differentiate into cells representing all three germ layers. The implications of this research extend to the potential development of novel treatments for Dent disease.
2017-03-15 | Nanotubes, the fast track to treatment of Dent disease?
Studies in mice have suggested bone marrow transplantation as a strategy to correct the endocytic dysfunction of the proximal tubules in renal Fanconi syndrome, yet the mode of action has remained mysterious. Using a mouse model of Dent disease, Gabriel et al. now show that rescue of the resorptive capacity in the diseased kidney involves cell-to-cell contact between engrafted and host cells via nanotubes, cellular projections that enable transfer of wild-type activity into mutant cells of the proximal tubule.
gene therapies
2026-03-10 | Database of CLCN5 Pathogenic Variants Causing Dent Disease
Introduction: Dent disease type 1 is an X-linked proximal tubulopathy caused by pathogenic variants in CLCN5, which encodes the chloride/proton exchanger ClC-5.Loss of ClC-5 function disrupts receptor-mediated endocytosis, resulting in low-molecular-weight proteinuria, hypercalciuria, nephrocalcinosis, nephrolithiasis, and progressive kidney failure.Although many CLCN5 variants have been reported, existing resources remain incomplete, inconsistent, or based on different reference sequences, hindering variant comparison and clinical interpretation.A comprehensive and uniformly annotated catalog is needed to improve diagnostic accuracy and estimates of Dent disease type 1 prevalence.Methods: Potentially pathogenic CLCN5 variants were compiled from firsthand Dent disease type 1 case reports, variant databases, Dent disease type 1-related online resources, and unpublished patients.Variants representing experimental constructs or benign/likely benign changes were excluded.All variants were standardized using HGVS nomenclature and mapped to reference sequences NM_001127898.4and NM_000084.5 with Mutalyzer.Pathogenicity was assessed and cross-validated with the literature and public databases. Results:We identified 524 unique pathogenic or likely pathogenic variants, exceeding all existing databases.Variant types included missense (31%), InDelinsertions and deletions (37%), nonsense (14%), splicing defects (13%), and large deletions (5%).Most variants (74%) were reported only once.Exon 10 (NM_001127898.4) showed the highest density of pathogenic variants, driven by missense and in-frame insertions and deletionsInDel.Structural mapping revealed functional restrained regions in Helix H and O-Q helices.Source-variant counts indicated a minimum of 880 affected families, suggesting ~3,520 globally. Conclusions:This uniformly annotated catalog-the most comprehensive to date-enhances interpretation of CLCN5 variants, refines Dent disease type 1 burden estimates, and identifies key functional regions relevant for therapeutic development.
2025-12-09 | Genetic and clinical phenotype of Dent disease in Chinese children and the etiological analysis of early - onset chronic kidney disease.
A prominent feature of Dent disease (DD) is the progressive decline in renal function, with 30% - 80% of male patients advancing to end-stage renal disease between the ages of 30 and 50 years. However, limited research exists on the chronic kidney disease (CKD) progression in pediatric patients with DD. This study aimed to retrospectively analyze the clinical features, genetic variant spectrum, and prognosis of pediatric patients with DD and explore the factors associated with early renal failure during childhood in these patients. We analyzed the genetic backgrounds, clinical phenotypes, and laboratory data of 23 unrelated patients with DD. All patients were males with low-molecular-weight proteinuria. CLCN5 variants were detected in 19 patients (Dent disease type 1, DD1), and OCRL variants were identified in 4 patients (Dent disease type 2, DD2). Sixteen mutations have not been reported previously. During follow-up, progression to CKD was documented in 7 patients: 6 with DD1 and 1 with DD2. CKD stages were distributed as follows: 4 patients at stage II, 2 at stage III, and 1 at stage V. Nephrolithiasis (100% vs 30.76%, P = 0.011), nephrocalcinosis (85.33% vs 15.38%, P = 0.010), and acute kideny injury (100% vs 0%, P < 0.001) were significantly more common in those CKD patients with DD1. This study expands the genetic spectrum of Dent disease and highlights that some pediatric patients may progress to CKD during childhood. CKD progression may be associated with early occurrences of nephrolithiasis, nephrocalcinosis, and acute kidney injury.
2025-10-01 | #3039 Etiological analysis of early-onset chronic kidney disease: a study on dent disease in chinese pediatric patients
Abstract Background and Aims Dent disease (DD) is a rare monogenic, X-linked recessive disorder characterized by proximal renal tubular dysfunction. The hallmark features include low-molecular-weight proteinuria (LMWP), hypercalciuria, nephrocalcinosis, nephrolithiasis, and progressive renal failure. A notable feature of Dent disease is the progressive decline in renal function, with 30% to 80% of male patients advancing to end-stage renal disease (ESRD) between the ages of 30 and 50. However, there is limited research detailing the progression of chronic kidney disease (CKD) in pediatric Dent disease patients. To date, European and Chinese cohorts have reported 44 and 4 cases, respectively, of childhood CKD associated with Dent disease. Though these cases lack detailed descriptions. In this study, we retrospectively analyzed the clinical characteristics, genetic variant spectrum, and follow-up data of 25 children with Dent disease. The aim was to explore the causes of CKD occurring during childhood in Dent disease and to raise awareness among pediatricians about this condition. Method We conducted a retrospective analysis of 25 patients diagnosed with Dent disease between 2012 and 2024 at the Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology. The study analyzed the genetic backgrounds, clinical phenotypes, and laboratory findings of these 25 unrelated patients. Results All pediatric patients in this cohort were male. Of the 25 patients, 19 (76.0%) were diagnosed with DD1, while 4 (16.0%) were diagnosed with DD2. The specific type of 2 patients (8.0%) could not be determined and were classified as Dent-not identified (Dent-NI). Low-molecular-weight proteinuria was present in all patients. There was no difference in clinical manifestations between DD1 patients and DD2 patients. All 25 patients underwent genetic testing. Variants in CLCN5 were detected in 19 patients, and OCRL variants were identified in 4 patients. No pathogenic variants were detected in the remaining 2 patients. For CLCN5, most variants were missense variants (31.6%), followed by frameshift (26.3%), nonsense (26.3%), deletion (10.5%) and splicing mutation (5.3%). Of these, 13 variants were novel. For OCRL, detected variants included missense variants (75.0%) and frame shift (25.0%), with 3 being previously unreported. The median follow-up duration was 4.7 ± 3.02 years and the median age of patients at the last follow-up was 9 ± 4.91 years. During follow-up, 7 patients progressed to CKD, with 4 in CKD stage II, 2 in stage III, and 1 in stage V, all these CKD patients had a history of acute kidney injury (AKI). Among DD1 patients, clinical phenotypes and genotypes were compared between those who developed chronic renal failure and those who did not. Significant differences were noted in the incidence of hypercalciuria (37.5% vs 100%, P = 0.031), nephrolithiasis (37.5% vs 100%, P = 0.031) and acute kidney injury (12.5% vs 83.33%, P = 0.026) between the two groups. Conclusion Our study expands the genetic spectrum of Dent disease and highlights the potential for CKD progression during childhood. Nephrolithiasis and AKI are critical risk factors for CKD progression, emphasizing the need for early diagnosis and proactive management. Further research on genotype-phenotype correlations and the development of targeted therapies is essential to improving outcomes for patients with Dent disease.
2025-05-27 | Phenotype and genotype analyses of 21 Chinese patients with Dent disease.
Dent disease is a rare X-linked recessively inherited renal tubulopathy, caused by variants in the CLCN5 (Dent disease type 1, DD1) and OCRL (Dent disease type 2, DD2) genes, and characterized by low molecular weight proteinuria, hypercalciuria, microscopic hematuria, or nephrocalcinosis. In the current study, we collected and analyzed clinical data and genetic testing results of 21 children diagnosed with Dent disease, who were hospitalized at the Department of Nephrology, Children's Hospital of Nanjing Medical University between January 2014 and August 2023, aiming to assist in the early diagnosis and treatment of these patients. Among the 21 patients, 16 (76.19%) had CLCN5 variants, and five (23.81%) had OCRL variants, and four of the variants were novel. All patients presented with low molecular weight proteinuria, 14 (66.67%) of whom had nephrotic-range proteinuria. Eight patients underwent renal biopsies because of diagnostic uncertainty. We transfected the novel CLCN5 missense variant (p.G222R) and OCRL missense variant (p.I371T) plasmids into both HEK293 and HK-2 cells and found a significantly lower expression of the OCRL1 protein in the transfected cells than in the wild-type cells ( P < 0.05). Moreover, we observed an extremely skewed X-chromosome inactivation pattern in a female patient carrying the same novel CLCN5 variant, as assessed by the human androgen receptor gene assay. These findings provide insight into the clinical characteristics of Dent disease in Chinese patients and may shed light on its pathogenesis.
2024-09-26 | Gene therapy of Dent disease type 1 in newborn ClC-5 null mice for sustained transgene expression and gene therapy effects.
Dent disease type 1 is caused by changes in the chloride voltage-gated channel 5 (CLCN5) gene on chromosome X, resulting in the lack or dysfunction of chloride channel ClC-5. Individuals affected by Dent disease type 1 show proteinuria and hypercalciuria. Previously we found that lentiviral vector-mediated hCLCN5 cDNA supplementary therapy in ClC-5 null mice was effective only for three months following gene delivery, and the therapeutic effects disappeared four months after treatment, most likely due to immune responses to the ClC-5 proteins expressed in the treated cells. Here we tried two strategies to reduce possible immune responses: 1) confining the expression of ClC-5 expression to the tubular cells with tubule-specific Npt2a and Sglt2 promoters, and 2) performing gene therapy in newborn mutant mice whose immune system has not fully developed. We found that although Npt2a and Sglt2 promoters successfully drove ClC-5 expression in the kidneys of the mutant mice, the treatment did not ameliorate the phenotypes. However, gene delivery to the kidneys of newborn Clcn5 mutant mice enabled long-term transgene expression and phenotype improvement. Our data suggest that performing gene therapy on Dent disease affected subjects soon after birth could be a promising strategy to attenuate immune responses in Dent disease type 1 gene therapy.
other
2026-09-01 | Abstract No: 531 A Novel CLCN5 Frameshift Variant (p.R788Afs*24) Unravels Dimerization and Ligand-Binding Defects in Dent Disease 1: Integrated Clinical–Genetic–Structural Study
Introduction: Medical History: A 48-year-old woman was admitted with "recurrent edema of both lower extremities for more than 1 year, aggravated for 10 days.Methods: Symptoms and Signs: On admission, the patient presented with moderate bilateral lower-extremity edema, decreased urine output with a 24-hour urine volume of 300-800 mL, massive foamy urine, hypertension with systolic blood pressure up to 210 mmHg, chest tightness, and dyspnea.Diagnosis: Renal biopsy revealed IgG3-λ proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID).Laboratory tests showed serum creatinine (SCr) of 378 μmol/L, estimated glomerular filtration rate (eGFR) of 17 mL/min/1.73m 2 , urinary albuminto-creatinine ratio (UACR) of 11,690 mg/gCr, 24-hour urinary protein excretion of 12.284 g/24 h, serum free λ light chain (sFLC-λ) of 81.4 mg/L, serum free κ light chain (sFLC-κ) of 59.9 mg/L, sFLC-κ/λ ratio of 0.711, and B-type natriuretic peptide (BNP) of 434.35 pg/mL.Results: Treatment: Conventional immunosuppressive regimens, including sequential combination therapy with dexamethasone, bortezomib, cyclophosphamide, and lenalidomide, showed poor efficacy.The regimen was therefore switched to the anti-CD38 monoclonal antibody daratumumab combined with low-dose prednisone (5 mg/day).Supportive symptomatic treatment included renal-protective therapy with Bailing capsules, antihypertensive therapy with nifedipine controlled-release tablets, terazosin hydrochloride tablets, and clonidine hydrochloride tablets, correction of anemia with roxadustat capsules and polysaccharide iron complex, and infection prophylaxis with compound sulfamethoxazole tablets and ganciclovir tablets.Clinical Outcome: After 6 months of treatment, edema and oliguria had completely resolved.SCr decreased to 206 μmol/L, representing a 45.5% reduction; UACR decreased to 4,563 mg/gCr, a 61.0%reduction; 24-hour urinary protein decreased to 4.872 g/day, a 60.3% reduction; and sFLC-λ decreased to 40 mg/L, a 50.6% reduction.The sFLC-κ/λ ratio, IgG, C3, C4, and BNP were all within normal ranges.No infusion-related reactions or severe infections occurred.Conclusion: Daratumumab may effectively improve IgG3-λ PGNMID complicated by severe renal impairment by targeting and eliminating pathogenic CD38 + plasma cells.It significantly ameliorated proteinuria and renal function in this patient, providing a new therapeutic option for patients with IgG3-λ PGNMID and severe renal impairment who respond poorly to conventional immunosuppressive therapy.
proteins
2026-04-01 | Use of recombinant growth hormone in the treatment of short stature in a sibling pair with Dent disease
ABSTRACT Dent disease (DD) is a rare X-linked recessive proximal tubulopathy characterized by low molecular-weight proteinuria, nephrolithiasis, and slowly progressive renal failure. It is caused by mutations in the chloride channel chloride voltage-gated channel 5 (CLCN5) or the oculocerebrorenal syndrome of Lowe gene. We describe two brothers with genetically confirmed DD type 1 due to a pathogenic CLCN5 duplication (c.351_352dupAA). The elder sibling, diagnosed 9 years after presenting with frothy urine, developed progressive growth retardation despite conventional therapy. At 15 years, his height was −3.5 standard deviation (SD) with a normal growth hormone (GH)–insulin-like growth factor-1 (IGF-1) axis. His younger brother, identified on family screening, had severe short stature (−4.1 SD) and documented GH deficiency on clonidine stimulation. After informed consent from parents, both received recombinant GH (rGH, 0.18 mg/kg/week) in addition to standard management for 1 year. They showed significant height gain without any complications of rGH therapy. Serum phosphate and tubular phosphate reabsorption improved, while renal function and calciuria remained stable. To conclude, short stature in DD is multifactorial, and GH deficiency may be one of the contributing factors. Conventional treatment often fails to address the issue of short stature in these patients. Treatment with rGH demonstrated improved growth velocity and suggests potential therapeutic benefits in these patients regardless of GH–IGF-1 axis function.
2024-07-18 | A novel transgenic mouse model highlights molecular disruptions involved in the pathogenesis of Dent disease 1.
Dent disease (DD) is a hereditary renal disorder characterized by low molecular weight (LMW) proteinuria and progressive renal failure. Inactivating mutations of the CLCN5 gene encoding the 2Cl-/H+exchanger ClC-5 have been identified in patients with DD type 1. ClC-5 is essentially expressed in proximal tubules (PT) where it is thought to play a role in maintaining an efficient endocytosis of LMW proteins. However, the exact pathological roles of ClC-5 in progressive dysfunctions observed in DD type 1 are still unclear. To address this issue, we designed a mouse model carrying the most representative type of ClC-5 missense mutations found in DD patients. These mice showed a characteristic DD type 1 phenotype accompanied by altered endo-lysosomal system and autophagy functions. With ageing, KI mice showed increased renal fibrosis, apoptosis and major changes in cell metabolic functions as already suggested in previous DD models. Furthermore, we made the interesting new discovery that the Lipocalin-2-24p3R pathway might be involved in the progression of the disease. These results suggest a crosstalk between the proximal and distal nephron in the pathogenesis mechanisms involved in DD with an initial PT impairment followed by the Lipocalin-2 internalisation and 24p3R overexpression in more distal segments of the nephron. This first animal model of DD carrying a pathogenic mutation of Clcn5 and our findings pave the way aimed at exploring therapeutic strategies to limit the consequences of ClC-5 disruption in patients with DD type 1 developing chronic kidney disease.
2018-12-24 | OCRL deficiency impairs endolysosomal function in a humanized mouse model for Lowe syndrome and Dent disease
Mutations in OCRL encoding the inositol polyphosphate 5-phosphatase OCRL (Lowe oculocerebrorenal syndrome protein) disrupt phosphoinositide homeostasis along the endolysosomal pathway causing dysfunction of the cells lining the kidney proximal tubule (PT). The dysfunction can be isolated (Dent disease 2) or associated with congenital cataracts, central hypotonia and intellectual disability (Lowe syndrome). The mechanistic understanding of Dent disease 2/Lowe syndrome remains scarce due to limitations of animal models of OCRL deficiency. Here, we investigate the role of OCRL in Dent disease 2/Lowe syndrome by using OcrlY/− mice, where the lethal deletion of the paralogue Inpp5b was rescued by human INPP5B insertion, and primary culture of proximal tubule cells (mPTCs) derived from OcrlY/− kidneys. The OcrlY/− mice show muscular defects with dysfunctional locomotricity and present massive urinary losses of low-molecular-weight proteins and albumin, caused by selective impairment of receptor-mediated endocytosis in PT cells. The latter was due to accumulation of phosphatidylinositol 4,5–bisphosphate PI(4,5)P2 in endolysosomes, driving local hyper-polymerization of F-actin and impairing trafficking of the endocytic LRP2 receptor, as evidenced in OcrlY/− mPTCs. The OCRL deficiency was also associated with a disruption of the lysosomal dynamic and proteolytic activity. Partial convergence of disease-pathways and renal phenotypes observed in OcrlY/− and Clcn5Y/− mice suggest shared mechanisms in Dent diseases 1 and 2. These studies substantiate the first mouse model of Lowe syndrome and give insights into the role of OCRL in cellular trafficking of multiligand receptors. These insights open new avenues for therapeutic interventions in Lowe syndrome and Dent disease.
2004-01-23 | Coexpression of complementary fragments of ClC-5 and restoration of chloride channel function in a Dent's disease mutation.
The human hereditary disorder Dent's disease is linked to loss-of-function mutations of the chloride channel ClC-5. Many of these mutations involve insertion of premature stop codons, resulting in truncation of the protein. We determined whether the functional activity of ClC-5 could be restored by coexpression of the truncated protein (containing the NH2-terminal region) with its complementary "missing" COOH-terminal region. Split channel constructs for ClC-5, consisting of complementary N and C protein regions, were created at an arbitrary site in the COOH-terminal region (V655) and at four Dent's disease mutation sites (R347, Y617, R648, and R704). Coexpression of complementary fragments for the split channel at V655 produced currents with anion and pH sensitivity similar to those of wild-type ClC-5. Channel activity was similarly restored when complementary split channel constructs made for Dent's mutation R648 were coexpressed, but no ClC-5 currents were found when split channels for mutations R347, Y617, or R704 were coexpressed. Immunoblot and immunofluorescence studies of COS-7 cells revealed that N or C protein fragments could be transiently expressed and detected in the plasma membrane, even in split channels that failed to show functional activity. The results suggest that ClC-5 channel activity can be restored for specific Dent's mutations by expression of the missing portion of the ClC-5 molecule.
small molecules
2026-07-07 | The Missense Mutant ClC-5 (E211A), associated with Proton/Chloride Uncoupling Exacerbates Renal Pathology Compared to the ClC-5 null Mutant.
Dent disease type 1 is an X-linked proximal tubulopathy caused by mutations in CLCN5, which encodes the chloride/proton exchanger ClC-5. While loss-of-function mutations impair endocytosis and lead to progressive renal disease, the pathological consequences of uncoupling mutations that selectively disrupt Cl-/H+ exchange remain incompletely understood. In this study, we examined the renal phenotype associated with the ClC-5 E211A uncoupling mutation, which abolishes proton transport while preserving chloride conductance, and compared it with that of ClC-5 null mice. Contrary to the expectation that partial transport activity would mitigate disease severity, E211A mutant mice developed more severe and progressive kidney pathology than null mutants. Both models exhibited early low-molecular-weight proteinuria, including marked urinary excretion of β2-microglobulin and vitamin D-binding protein. However, E211A mutants displayed progressive polyuria, reduced body weight, and pronounced interstitial fibrosis at 5 and 18 months of age, changes not observed in ClC-5 null mice. Renal injury in E211A mutants was characterized by glomerular abnormalities, including enlarged Bowman's spaces, cyst formation, reduced podocyte markers Wilms tumor protein and nephrin, and age-dependent tubular degeneration. ClC-5 E211A protein showed altered localization and reduced expression in vivo, suggesting disrupted trafficking or stability. Phenotypic severity was strongly influenced by genetic background, underscoring its modulatory role in disease expression. Together, these findings demonstrate that the ClC-5 E211A uncoupling mutation induces additional adverse effects that exceed those caused by complete loss of ClC-5. Our results reveal that uncoupling mutations can drive progressive kidney damage through mechanisms distinct from gene knockout and highlight the need for mutation-specific therapeutic strategies for Dent disease type 1.
2026-02-27 | The Significance of Fibroblast Growth Factor 23 and 24,25-Dihydroxyvitamin D in Dent Disease Type 1.
Fibroblast growth factor 23 and 24,25-dihydroxyvitamin D are positively correlated and are significantly lower in Dent disease than in idiopathic calcium kidney stones patients. Dent patients with low 24,25-dihydroxyvitamin D had greater hypercalciuria and proteinuria, and, among adults, higher 1,25-dihydroxyvitamin D concentrations. Moderate phosphate supplementation mitigates hypercalciuria. Hypercalciuria is a prominent characteristic in Dent disease type 1 (DD1) and is associated with kidney stones and nephrocalcinosis. The objectives of this study were to assess fibroblast growth factor 23 (FGF23) and 24,25-dihydroxyvitamin D (24,25(OH) 2 D) in DD1 patients and investigate the effects of phosphate supplementation on urinary calcium excretion. Serum and 24-hour urine assessments from adult and pediatric DD1 patients ( N =10 adults; N =9 pediatrics) were compared with adult control subjects with a history of idiopathic calcium kidney stones and hypercalciuria ( N =9). Adult DD1 patients and control participants completed an oral phosphate supplementation intervention (1 g/d×14 days) with reassessment immediately after intervention. FGF23 was significantly lower in DD1 than in the control cohort (adults, P = 0.006) and positively correlated with 24,25(OH) 2 D across all study cohorts. The concentrations of 24,25(OH) 2 D were low with conversion ratios (25-hydroxyvitamin D: 24,25(OH) 2 D) exceeding the clinical reference limit for five of 10 adults and six of 9 pediatric DD1 patients. The DD1 cohorts were then stratified by the 24,25(OH) 2 D ratio into "normal" and "low" 24,25(OH) 2 D. Adult DD1 patients with low 24,25(OH) 2 D ( n =5) had lower FGF23, higher 1,25-dihydroxyvitamin D, greater urine calcium, and greater urine protein. Pediatric stratified data mirrored that in adults with the exception of no difference in serum 1,25-dihydroxyvitamin D. Phosphate supplementation was effective in decreasing urine calcium in both adult DD1 and control adult cohorts. Clinical measurement of 24,25(OH) 2 D is a novel and useful analysis for evaluating the severity of calcium and protein dysregulation in DD1. In addition, moderate phosphate supplementation effectively mitigates urine calcium excretion in DD1 adult patients. ClinicalTrials.gov, NCT02016235 .
2025-10-01 | Native Kidney Embolization as Minimally Invasive Treatment for Post-Transplant Polyuria
Introduction: High native kidney urine output post-transplant can lead to dehydration, poor graft perfusion, and increased risk of acute kidney injuries. We describe native kidney embolization as an effective, less invasive, lower morbidity alternative to nephrectomy for patients with post-transplant polyuria. Case Description: Seven patients ages 4 to 19 with renal disease from Bardet-Biedl syndrome, Dent disease, primary hyperoxaluria type 1, renal cortical necrosis, and obstructive uropathy underwent post-transplant native kidney embolization for high urine output. Barriers to performing nephrectomy included horseshoe kidney, elevated BMI, surgical history, and behavioral concerns. Interventional Radiology performed all embolizations via a femoral approach. Angiogram was performed to assess anatomy, followed by ethanol and coil embolization, with repeat angiogram after to ensure success. All patients received a short steroid taper for prevention of post-embolization syndrome. Hospital length of stay was 4-8 days post-embolization. Three patients required ICU stay for sedation during lay flat time post-procedure. Pain was overall well-controlled. Six of seven had lower 24-hour fluid intake requirements post-embolization, with subjective reports of 50-75% decrease in urine output from one patient, and decrease in overnight diapers from another. Half had improvement in GFR post-procedure. Patients with prior hospitalizations for acute kidney injury from dehydration had a decrease in these episodes post-embolization. One patient with primary hyperoxaluria had continued decline in plasma oxalate levels post-embolization. Discussion: This case series demonstrates that native kidney embolization was successful and well tolerated. Pain was well-controlled, with no significant complications from the procedure. Half of the patients experienced improved GFR, and multiple patients reported subjective decrease in urine output after the procedure. Native kidney embolization can be considered an effective, less invasive and lower morbidity alternative to nephrectomy for patients with post-transplant polyuria.
2024-08-28 | [Two cases of Dent disease type 1 with Bartter-like phenotype and literature review].
The clinical presentation, treatment, and follow-up of two boys with type 1 Dent disease who exhibited a Bartter-like phenotype were retropectively analysed. The related literature of pediatric patients with type 1 Dent disease who had hypokalemia and metabolic alkalosis was screened through databases such as PubMed, CNKI, and Wanfang until February 1, 2024, and common features among these patients were summarized through literature review. A total of 7 literatures were included, and 9 children were included in the analysis. All patients were male, presenting with significant low molecular weight proteinuria and hypercalciuria. Other prominent characteristic phenotypes included short stature (7/8), hypophosphatemia (8/9), and rickets (6/8). Seven previously reported patients had missense or nonsense mutations, while 2 patients in this study carried possible pathogenic mutations in the CLCN5 gene, c.315+2T>A (p.?) and c.584dupT (p.I196Yfs*6), respectively. Five patients were able to maintain blood potassium levels around 3 mmol/L with oral potassium chloride solution combined with non-steroidal anti-inflammatory drugs (ibuprofen or indomethacin). The follow-up showed that 2 patients developed chronic kidney disease stage 4 and stage 3 at the age of 13 and 21 years, respectively. The phenotypic overlap between Dent disease and Batter syndrome is considerable,with the distinguishing feature being the presence of significant low molecular weight proteinuria. Patients with type 1 Dent disease presenting with the Bartter-like phenotype have a high prevalence of short stature, hypophosphatemia, and rickets. Non-steroidal anti-inflammatory drugs can be used to correct hypokalemia in patients under periodic renal function assessment. 回顾性分析2例以巴特样表型起病的登特病1型男性患儿的临床表现、治疗及随访。检索PubMed、知网、万方等数据库，从建库至2024年2月1日，筛选低钾血症合并代谢性碱中毒的登特病1型患儿相关文献，通过文献复习总结此病患儿的临床特征。纳入7篇文献，9例患儿纳入分析。患者均为男性，均有大量低分子蛋白尿和高钙尿症，其他突出的特征性表型包括身材矮小（7/8）、低磷血症（8/9）及佝偻病（6/8）。已报道的7例患者为CLCN5基因错义或无义突变，本研究报道的2例患者分别携带CLCN5基因可能致病性突变：c.315+2T>A（p.？）及c.584dupT（p.I196Yfs*6）。5例患者经氯化钾口服液联合非甾体类抗炎药（布洛芬或吲哚美辛）能维持血钾水平在3 mmol/L左右。随访显示有2例患者分别在13和21岁时出现慢性肾脏病4期和3期。登特病与巴特综合征表型重合度高，鉴别点在于是否存在大量低分子蛋白尿。以巴特样表型起病的登特病1型患者身材矮小、低磷血症及佝偻病的发生率高。在定期检测肾功能的情况下，非甾体抗炎药可用于纠正患者的低钾血症。.
2024-08-10 | 4-Phenylbutyric Acid Treatment Reduces Low-Molecular-Weight Proteinuria in a Clcn5 Knock-in Mouse Model for Dent Disease-1.
Dent disease-1 (DD-1) is a rare X-linked tubular disorder characterized by low-molecular-weight proteinuria (LMWP), hypercalciuria, nephrolithiasis and nephrocalcinosis. This disease is caused by inactivating mutations in the CLCN5 gene which encodes the voltage-gated ClC-5 chloride/proton antiporter. Currently, the treatment of DD-1 is only supportive and focused on delaying the progression of the disease. Here, we generated and characterized a Clcn5 knock-in mouse model that carries a pathogenic CLCN5 variant, c. 1566_1568delTGT; p.Val523del, which has been previously detected in several DD-1 unrelated patients, and presents the main clinical manifestations of DD-1 such as high levels of urinary b2-microglobulin, phosphate and calcium. Mutation p.Val523del causes partial ClC-5 retention in the endoplasmic reticulum. Additionally, we assessed the ability of sodium 4-phenylbutyrate, a small chemical chaperone, to ameliorate DD-1 symptoms in this mouse model. The proposed model would be of significant value in the investigation of the fundamental pathological processes underlying DD-1 and in the development of effective therapeutic strategies for this rare condition.
cell therapies
2023-09-08 | Generation of a human induced pluripotent stem cell line from a patient with dent disease.
Dent disease, an X-linked tubular disorder, is a rare condition that leads to low-molecular-weight proteinuria, hypercalciuria, kidney stones, and chronic kidney disease. Here, we successfully established a human induced pluripotent stem cells (hiPSC) line from peripheral blood mononuclear cells of 10-year-old male with Dent disease 1 caused by the mutation of Chloride Voltage-Gated Channel 5 gene. This hiPSCs displayed features similar to human embryonic stem cells, including pluripotency-associated markers expression, normal karyotype, and the ability to differentiate into cells representing all three germ layers. The implications of this research extend to the potential development of novel treatments for Dent disease.
2017-03-15 | Nanotubes, the fast track to treatment of Dent disease?
Studies in mice have suggested bone marrow transplantation as a strategy to correct the endocytic dysfunction of the proximal tubules in renal Fanconi syndrome, yet the mode of action has remained mysterious. Using a mouse model of Dent disease, Gabriel et al. now show that rescue of the resorptive capacity in the diseased kidney involves cell-to-cell contact between engrafted and host cells via nanotubes, cellular projections that enable transfer of wild-type activity into mutant cells of the proximal tubule.
gene therapies
2026-03-10 | Database of CLCN5 Pathogenic Variants Causing Dent Disease
Introduction: Dent disease type 1 is an X-linked proximal tubulopathy caused by pathogenic variants in CLCN5, which encodes the chloride/proton exchanger ClC-5.Loss of ClC-5 function disrupts receptor-mediated endocytosis, resulting in low-molecular-weight proteinuria, hypercalciuria, nephrocalcinosis, nephrolithiasis, and progressive kidney failure.Although many CLCN5 variants have been reported, existing resources remain incomplete, inconsistent, or based on different reference sequences, hindering variant comparison and clinical interpretation.A comprehensive and uniformly annotated catalog is needed to improve diagnostic accuracy and estimates of Dent disease type 1 prevalence.Methods: Potentially pathogenic CLCN5 variants were compiled from firsthand Dent disease type 1 case reports, variant databases, Dent disease type 1-related online resources, and unpublished patients.Variants representing experimental constructs or benign/likely benign changes were excluded.All variants were standardized using HGVS nomenclature and mapped to reference sequences NM_001127898.4and NM_000084.5 with Mutalyzer.Pathogenicity was assessed and cross-validated with the literature and public databases. Results:We identified 524 unique pathogenic or likely pathogenic variants, exceeding all existing databases.Variant types included missense (31%), InDelinsertions and deletions (37%), nonsense (14%), splicing defects (13%), and large deletions (5%).Most variants (74%) were reported only once.Exon 10 (NM_001127898.4) showed the highest density of pathogenic variants, driven by missense and in-frame insertions and deletionsInDel.Structural mapping revealed functional restrained regions in Helix H and O-Q helices.Source-variant counts indicated a minimum of 880 affected families, suggesting ~3,520 globally. Conclusions:This uniformly annotated catalog-the most comprehensive to date-enhances interpretation of CLCN5 variants, refines Dent disease type 1 burden estimates, and identifies key functional regions relevant for therapeutic development.
2025-12-09 | Genetic and clinical phenotype of Dent disease in Chinese children and the etiological analysis of early - onset chronic kidney disease.
A prominent feature of Dent disease (DD) is the progressive decline in renal function, with 30% - 80% of male patients advancing to end-stage renal disease between the ages of 30 and 50 years. However, limited research exists on the chronic kidney disease (CKD) progression in pediatric patients with DD. This study aimed to retrospectively analyze the clinical features, genetic variant spectrum, and prognosis of pediatric patients with DD and explore the factors associated with early renal failure during childhood in these patients. We analyzed the genetic backgrounds, clinical phenotypes, and laboratory data of 23 unrelated patients with DD. All patients were males with low-molecular-weight proteinuria. CLCN5 variants were detected in 19 patients (Dent disease type 1, DD1), and OCRL variants were identified in 4 patients (Dent disease type 2, DD2). Sixteen mutations have not been reported previously. During follow-up, progression to CKD was documented in 7 patients: 6 with DD1 and 1 with DD2. CKD stages were distributed as follows: 4 patients at stage II, 2 at stage III, and 1 at stage V. Nephrolithiasis (100% vs 30.76%, P = 0.011), nephrocalcinosis (85.33% vs 15.38%, P = 0.010), and acute kideny injury (100% vs 0%, P < 0.001) were significantly more common in those CKD patients with DD1. This study expands the genetic spectrum of Dent disease and highlights that some pediatric patients may progress to CKD during childhood. CKD progression may be associated with early occurrences of nephrolithiasis, nephrocalcinosis, and acute kidney injury.
2025-10-01 | #3039 Etiological analysis of early-onset chronic kidney disease: a study on dent disease in chinese pediatric patients
Abstract Background and Aims Dent disease (DD) is a rare monogenic, X-linked recessive disorder characterized by proximal renal tubular dysfunction. The hallmark features include low-molecular-weight proteinuria (LMWP), hypercalciuria, nephrocalcinosis, nephrolithiasis, and progressive renal failure. A notable feature of Dent disease is the progressive decline in renal function, with 30% to 80% of male patients advancing to end-stage renal disease (ESRD) between the ages of 30 and 50. However, there is limited research detailing the progression of chronic kidney disease (CKD) in pediatric Dent disease patients. To date, European and Chinese cohorts have reported 44 and 4 cases, respectively, of childhood CKD associated with Dent disease. Though these cases lack detailed descriptions. In this study, we retrospectively analyzed the clinical characteristics, genetic variant spectrum, and follow-up data of 25 children with Dent disease. The aim was to explore the causes of CKD occurring during childhood in Dent disease and to raise awareness among pediatricians about this condition. Method We conducted a retrospective analysis of 25 patients diagnosed with Dent disease between 2012 and 2024 at the Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology. The study analyzed the genetic backgrounds, clinical phenotypes, and laboratory findings of these 25 unrelated patients. Results All pediatric patients in this cohort were male. Of the 25 patients, 19 (76.0%) were diagnosed with DD1, while 4 (16.0%) were diagnosed with DD2. The specific type of 2 patients (8.0%) could not be determined and were classified as Dent-not identified (Dent-NI). Low-molecular-weight proteinuria was present in all patients. There was no difference in clinical manifestations between DD1 patients and DD2 patients. All 25 patients underwent genetic testing. Variants in CLCN5 were detected in 19 patients, and OCRL variants were identified in 4 patients. No pathogenic variants were detected in the remaining 2 patients. For CLCN5, most variants were missense variants (31.6%), followed by frameshift (26.3%), nonsense (26.3%), deletion (10.5%) and splicing mutation (5.3%). Of these, 13 variants were novel. For OCRL, detected variants included missense variants (75.0%) and frame shift (25.0%), with 3 being previously unreported. The median follow-up duration was 4.7 ± 3.02 years and the median age of patients at the last follow-up was 9 ± 4.91 years. During follow-up, 7 patients progressed to CKD, with 4 in CKD stage II, 2 in stage III, and 1 in stage V, all these CKD patients had a history of acute kidney injury (AKI). Among DD1 patients, clinical phenotypes and genotypes were compared between those who developed chronic renal failure and those who did not. Significant differences were noted in the incidence of hypercalciuria (37.5% vs 100%, P = 0.031), nephrolithiasis (37.5% vs 100%, P = 0.031) and acute kidney injury (12.5% vs 83.33%, P = 0.026) between the two groups. Conclusion Our study expands the genetic spectrum of Dent disease and highlights the potential for CKD progression during childhood. Nephrolithiasis and AKI are critical risk factors for CKD progression, emphasizing the need for early diagnosis and proactive management. Further research on genotype-phenotype correlations and the development of targeted therapies is essential to improving outcomes for patients with Dent disease.
2025-05-27 | Phenotype and genotype analyses of 21 Chinese patients with Dent disease.
Dent disease is a rare X-linked recessively inherited renal tubulopathy, caused by variants in the CLCN5 (Dent disease type 1, DD1) and OCRL (Dent disease type 2, DD2) genes, and characterized by low molecular weight proteinuria, hypercalciuria, microscopic hematuria, or nephrocalcinosis. In the current study, we collected and analyzed clinical data and genetic testing results of 21 children diagnosed with Dent disease, who were hospitalized at the Department of Nephrology, Children's Hospital of Nanjing Medical University between January 2014 and August 2023, aiming to assist in the early diagnosis and treatment of these patients. Among the 21 patients, 16 (76.19%) had CLCN5 variants, and five (23.81%) had OCRL variants, and four of the variants were novel. All patients presented with low molecular weight proteinuria, 14 (66.67%) of whom had nephrotic-range proteinuria. Eight patients underwent renal biopsies because of diagnostic uncertainty. We transfected the novel CLCN5 missense variant (p.G222R) and OCRL missense variant (p.I371T) plasmids into both HEK293 and HK-2 cells and found a significantly lower expression of the OCRL1 protein in the transfected cells than in the wild-type cells ( P < 0.05). Moreover, we observed an extremely skewed X-chromosome inactivation pattern in a female patient carrying the same novel CLCN5 variant, as assessed by the human androgen receptor gene assay. These findings provide insight into the clinical characteristics of Dent disease in Chinese patients and may shed light on its pathogenesis.
2024-09-26 | Gene therapy of Dent disease type 1 in newborn ClC-5 null mice for sustained transgene expression and gene therapy effects.
Dent disease type 1 is caused by changes in the chloride voltage-gated channel 5 (CLCN5) gene on chromosome X, resulting in the lack or dysfunction of chloride channel ClC-5. Individuals affected by Dent disease type 1 show proteinuria and hypercalciuria. Previously we found that lentiviral vector-mediated hCLCN5 cDNA supplementary therapy in ClC-5 null mice was effective only for three months following gene delivery, and the therapeutic effects disappeared four months after treatment, most likely due to immune responses to the ClC-5 proteins expressed in the treated cells. Here we tried two strategies to reduce possible immune responses: 1) confining the expression of ClC-5 expression to the tubular cells with tubule-specific Npt2a and Sglt2 promoters, and 2) performing gene therapy in newborn mutant mice whose immune system has not fully developed. We found that although Npt2a and Sglt2 promoters successfully drove ClC-5 expression in the kidneys of the mutant mice, the treatment did not ameliorate the phenotypes. However, gene delivery to the kidneys of newborn Clcn5 mutant mice enabled long-term transgene expression and phenotype improvement. Our data suggest that performing gene therapy on Dent disease affected subjects soon after birth could be a promising strategy to attenuate immune responses in Dent disease type 1 gene therapy.
other
2026-09-01 | Abstract No: 531 A Novel CLCN5 Frameshift Variant (p.R788Afs*24) Unravels Dimerization and Ligand-Binding Defects in Dent Disease 1: Integrated Clinical–Genetic–Structural Study
Introduction: Medical History: A 48-year-old woman was admitted with "recurrent edema of both lower extremities for more than 1 year, aggravated for 10 days.Methods: Symptoms and Signs: On admission, the patient presented with moderate bilateral lower-extremity edema, decreased urine output with a 24-hour urine volume of 300-800 mL, massive foamy urine, hypertension with systolic blood pressure up to 210 mmHg, chest tightness, and dyspnea.Diagnosis: Renal biopsy revealed IgG3-λ proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID).Laboratory tests showed serum creatinine (SCr) of 378 μmol/L, estimated glomerular filtration rate (eGFR) of 17 mL/min/1.73m 2 , urinary albuminto-creatinine ratio (UACR) of 11,690 mg/gCr, 24-hour urinary protein excretion of 12.284 g/24 h, serum free λ light chain (sFLC-λ) of 81.4 mg/L, serum free κ light chain (sFLC-κ) of 59.9 mg/L, sFLC-κ/λ ratio of 0.711, and B-type natriuretic peptide (BNP) of 434.35 pg/mL.Results: Treatment: Conventional immunosuppressive regimens, including sequential combination therapy with dexamethasone, bortezomib, cyclophosphamide, and lenalidomide, showed poor efficacy.The regimen was therefore switched to the anti-CD38 monoclonal antibody daratumumab combined with low-dose prednisone (5 mg/day).Supportive symptomatic treatment included renal-protective therapy with Bailing capsules, antihypertensive therapy with nifedipine controlled-release tablets, terazosin hydrochloride tablets, and clonidine hydrochloride tablets, correction of anemia with roxadustat capsules and polysaccharide iron complex, and infection prophylaxis with compound sulfamethoxazole tablets and ganciclovir tablets.Clinical Outcome: After 6 months of treatment, edema and oliguria had completely resolved.SCr decreased to 206 μmol/L, representing a 45.5% reduction; UACR decreased to 4,563 mg/gCr, a 61.0%reduction; 24-hour urinary protein decreased to 4.872 g/day, a 60.3% reduction; and sFLC-λ decreased to 40 mg/L, a 50.6% reduction.The sFLC-κ/λ ratio, IgG, C3, C4, and BNP were all within normal ranges.No infusion-related reactions or severe infections occurred.Conclusion: Daratumumab may effectively improve IgG3-λ PGNMID complicated by severe renal impairment by targeting and eliminating pathogenic CD38 + plasma cells.It significantly ameliorated proteinuria and renal function in this patient, providing a new therapeutic option for patients with IgG3-λ PGNMID and severe renal impairment who respond poorly to conventional immunosuppressive therapy.
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