RARE DISEASE
Dent disease type 1
Dent disease type 1
Dent disease type 1
Drug discovery
0
drugs
With orphan designations
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
22 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:
22 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:
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.
2026-04-01 | 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.
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.
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 .
2025-12-09 | 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.
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.
2026-04-01 | 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.
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.
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 .
2025-12-09 | 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.
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