Dent's disease, an X-linked recessive disorder predominantly affecting males, is characterized by nephrocalcinosis, nephrolithiasis, and a high risk of progression to end-stage renal disease. Dent's disease type 1, accounting for 60% of cases, caused by mutations in the CLCN5 gene encoding the chloride ion channel protein ClC-5, exhibits significant clinical heterogeneity and variability in disease progression. The lack of hotspot mutations poses challenges for genetic diagnosis and counselling, complicating the prediction of disease outcomes. This study systematically evaluated the functional and structural impacts of 181 CLCN5 missense mutations using computational tools, including PredictSNP, MAGPIE, and molecular dynamics simulations, to propose a robust method for improving genetic counselling and prognosis prediction. Our analysis identified mutations at the dimer interface and chloride selectivity filter as critical disruptors of ClC-5 function and stability. Notably, molecular dynamics simulations of L200R, P213L, and G512R mutations revealed that L200R significantly destabilized the protein structure. Clinical data from a multicentre cohort of Chinese patients with CLCN5 mutations corroborated our computational predictions, highlighting the essential role of helix O in ClC-5 function. By integrating bioinformatics analyses with clinical validation, this study provides molecular insights into Dent's disease heterogeneity and proposes a framework for enhancing genetic counselling and prognostic assessment for affected patients.

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)2D) 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 to 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 (1g/day x 14 days) with reassessment immediately following intervention. FGF23 was significantly lower in DD1 than in the control cohort (adults, p=0.006) and positively correlated with 24,25(OH)2D across all study cohorts. The concentrations of 24,25(OH)2D were low with conversion ratios (25-hydroxyvitamin D:24,25(OH)2D) exceeding the clinical reference limit for five of 10 adults and six of nine pediatric DD1 patients. The DD1 cohorts were then stratified by the 24,25(OH)2D ratio into "normal" and "low" 24,25(OH)2D. Adult DD1 patients with low 24,25(OH)2D (n=5) had lower FGF23, higher 1,25(OH)2D, greater urine calcium, and greater urine protein. Pediatric stratified data mirrored that in adults with the exception of no difference in serum 1,25(OH)2D. Phosphate supplementation was effective in decreasing urine calcium in both adult DD1 and control adult cohorts. Clinical measurement of 24,25(OH)2D 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.

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.

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.

Dent disease type 1 (Dent 1) is a rare X-linked genetic condition which impacts kidney function and is caused by pathogenic variants in CLCN5. Affected males typically develop low molecular weight proteinuria, hypercalciuria, nephrocalcinosis, nephrolithiasis, and other symptoms. Kidney failure often occurs between the third to fifth decade of life. Here, we report an 11-year-old boy with Dent 1 and a severe kidney disease phenotype. The patient presented with flank pain, nocturnal enuresis, foamy urine, and increased urinary frequency. He was found to have nephrotic-range proteinuria, without hypoalbuminemia, and a significantly decreased estimated glomerular filtration rate at presentation. Further, he did not have hypercalciuria. His family history was remarkable for kidney disease among several relatives including a maternal half-brother and two sons of a maternal great aunt. Due to his symptoms and a strong family history, the patient underwent genetic testing that detected a novel pathogenic variant in CLCN5 [c.791dup (p.Ser265Glnfs*3)]. Given the variability of symptoms among family members and the early onset of severe symptoms in this young patient compared to prior literature, we encourage genetic testing for Dent disease in similarly affected individuals.