RESUMO
OBJECTIVE: The clinical characteristics, genetic mutation spectrum, treatment strategies and prognoses of 15 children with Dent disease were retrospectively analyzed to improve pediatricians' awareness of and attention to this disease. METHODS: We analyzed the clinical and laboratory data of 15 Chinese children with Dent disease who were diagnosed and treated at our hospital between January 2017 and May 2023 and evaluated the expression of the CLCN5 and OCRL1 genes. RESULTS: All 15 patients were male and complained of proteinuria, and the incidence of low-molecular-weight proteinuria (LMWP) was 100.0% in both Dent disease 1 (DD1) and Dent disease 2 (DD2) patients. The incidence of hypercalciuria was 58.3% (7/12) and 66.7% (2/3) in DD1 and DD2 patients, respectively. Nephrocalcinosis and nephrolithiasis were found in 16.7% (2/12) and 8.3% (1/12) of DD1 patients, respectively. Renal biopsy revealed focal segmental glomerulosclerosis (FSGS) in 1 patient, minimal change lesion in 5 patients, and small focal acute tubular injury in 1 patient. A total of 11 mutations in the CLCN5 gene were detected, including 3 missense mutations (25.0%, c.1756C > T, c.1166T > G, and c.1618G > A), 5 frameshift mutations (41.7%, c.407delT, c.1702_c.1703insC, c.137delC, c.665_666delGGinsC, and c.2200delG), and 3 nonsense mutations (25.0%, c.776G > A, c.1609C > T, and c.1152G > A). There was no significant difference in age or clinical phenotype among patients with different mutation types (p > 0.05). All three mutations in the OCRL1 gene were missense mutations (c.1477C > T, c.952C > T, and c.198A > G). CONCLUSION: Pediatric Dent disease is often misdiagnosed. Protein electrophoresis and genetic testing can help to provide an early and correct diagnosis.
Assuntos
Canais de Cloreto , Doença de Dent , Monoéster Fosfórico Hidrolases , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , China/epidemiologia , Canais de Cloreto/genética , Doença de Dent/genética , Doença de Dent/diagnóstico , População do Leste Asiático , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Testes Genéticos , Glomerulosclerose Segmentar e Focal/genética , Hipercalciúria/genética , Rim/patologia , Mutação , Mutação de Sentido Incorreto , Nefrocalcinose/genética , Nefrolitíase/genética , Monoéster Fosfórico Hidrolases/genética , Proteinúria/genética , Estudos RetrospectivosRESUMO
Dent disease type 1 is characterized by pathogenic CLCN5 gene variants and impaired receptor-mediated endocytosis in proximal tubules. However, mutation-related abnormalities in proximal tubules have not yet been described. Here, we present three patients with CLCN5 alterations and distinct morphological changes of the apical endocytic-lysosomal apparatus. The proximal tubular ultrastructure was investigated in kidney biopsy samples of three boys genotyped for non-nephrotic proteinuria. Controls: seven patients with nephrotic-range glomerular proteinuria. The genotyping findings revealed an already-known missense mutation in one patient and hitherto undescribed frameshift variants in two patients. Low-molecular-weight proteinuria, focal global glomerulosclerosis, proximal tubular changes, and tubular calcium deposits characterized each case. Three subsets of proximal tubular cells were observed: those without any abnormality, those with aplasia of apical endocytic-lysosomal apparatus and shrinkage of cells, and those with hypoplasia of apical endocytic apparatus, accumulation of proteinaceous substance in dysmorphic lysosomes, and dysmorphic mitochondria. The distribution of subsets varied from patient to patient. In one patient with a frameshift variant, an oxidative stress-like injury of proximal tubular cells and podocytes accompanied the above-mentioned alterations. Focal aplasia/hypoplasia of apical endocytic apparatus and subsequent changes in cytoplasmic organelles characterized proximal tubules in the CLCN5 pathogenic variants.
Assuntos
Glomerulosclerose Segmentar e Focal , Lisossomos , Masculino , Humanos , Mutação , Mutação da Fase de Leitura , Mutação de Sentido Incorreto , ProteinúriaRESUMO
INTRODUCTION: Dent disease type I is a rare X-linked recessive renal tubular disease resulting from pathogenic variants in the CLCN5 gene. Due to the rarity of Dent disease type I and the diversity of its phenotypes, its clinical diagnosis is complex and poses a challenge to clinicians. METHODS: A foetus and a child from a 36-year-old pregnant woman with a birth history of abnormal children were enrolled in this study. Pregnant women undergo amniocentesis for prenatal diagnosis at the gestational age of 12+ 3 weeks. Chromosomal microarray (CMA) analysis and whole-exome sequencing (WES) were employed to investigate the chromosomal copy number and single gene variants. Literature retrieval and data analysis were performed for genotype and phenotype collection analysis. RESULTS: No chromosomal abnormalities or CNVs were detected in the entire family through karyotype and familial CMA analyses. WES identified a nonsense pathogenic variant in CLCN5 of the X chromosome, c.1942 C > T (exon 11, NM_000084), which was inherited from his mother, who exhibited regular clinical features. CONCLUSION: This study suggests that children with low-molecular-weight proteinuria and hypercalciuria should undergo prompt genetic testing to exclude Dent disease.
Assuntos
Doença de Dent , Adulto , Feminino , Humanos , Gravidez , Aberrações Cromossômicas , Cromossomos Humanos X , Testes Genéticos , Diagnóstico Pré-NatalRESUMO
Dent disease is a rare renal tubular disease with X-linked recessive inheritance characterized by low molecular weight proteinuria (LMWP), hypercalciuria, and nephrocalcinosis. Mutations disrupting the 2Cl-/1H+ exchange activity of chloride voltage-gated channel 5 (CLCN5) have been causally linked to the most common form, Dent disease 1 (DD1), although the pathophysiological mechanisms remain unclear. Here, we conducted the whole exome capture sequencing and bioinformatics analysis within our DD1 cohort to identify two novel causal mutations in CLCN5 (c.749 G > A, p. G250D, c.829 A > C, p. T277P). Molecular dynamics simulations of ClC-5 homology model suggested that these mutations potentially may induce structural changes, destabilizing ClC-5. Overexpression of variants in vitro revealed aberrant subcellular localization in the endoplasmic reticulum (ER), significant accumulation of insoluble aggregates, and disrupted ion transport function in voltage clamp recordings. Moreover, human kidney-2 (HK-2) cells overexpressing either G250D or T277P displayed higher cell-substrate adhesion, migration capability but reduced endocytic function, as well as substantially altered transcriptomic profiles with G250D resulting in stronger deleterious effects. These cumulative findings supported pathogenic role of these ClC-5 mutations in DD1 and suggested a cellular mechanism for disrupted renal function in Dent disease patients, as well as a potential target for diagnostic biomarker or therapeutic strategy development.
Assuntos
Doença de Dent , Doenças Genéticas Ligadas ao Cromossomo X , Nefrolitíase , Humanos , Doença de Dent/genética , Doença de Dent/patologia , Nefrolitíase/genética , Mutação , Transporte de ÍonsRESUMO
This study highlights the importance of a combined diagnostic approach in the diagnosis of rare diseases, such as adult-onset genetic FSGS. We present three adult patient cases evaluated with kidney biopsy for proteinuria, chronic kidney disease, and hypertension, which were suggestive of adult-onset genetic FSGS. Renal biopsy samples and formalin-fixed, paraffin-embedded fetal kidneys were evaluated using standard light microscopical stainings, direct immunofluorescence on cryostat sections, and electron microscopy. Clinical exome sequencing was performed for each case, and 45 FSGS-related genes were analyzed. Identifying mutations in the PAX2, ACTN4, and COL4A5 genes have prompted a re-evaluation of the previous histopathological examinations. The PAX2 mutation led to a thinner nephrogenic zone and decreased number of glomeruli, resulting in oligohydramnios during fetal development and oligomeganephronia and adaptive focal-segmental glomerulosclerosis in adulthood. The ACTN4 mutation caused distinct electron-dense aggregates in podocyte cell bodies, while the COL4A5 mutation led to segmental sclerosis of glomeruli with marked interstitial fibrosis and tubular atrophy. The identification of specific mutations and their histopathological consequences can lead to a better understanding of the disease and its progression, as well as potential treatment options.
Assuntos
Glomerulosclerose Segmentar e Focal , Adulto , Humanos , Glomerulosclerose Segmentar e Focal/diagnóstico , Glomerulosclerose Segmentar e Focal/genética , Glomerulosclerose Segmentar e Focal/patologia , Glomérulos Renais/patologia , Mutação , Fenótipo , GenótipoRESUMO
Dent disease (DD) is an X-linked renal tubulopathy characterized by low-molecular-weight proteinuria, hypercalciuria, nephrocalcinosis, nephrolithiasis and progressive renal failure. Two-thirds of cases are associated with inactivating variants in the CLCN5 gene (Dent disease 1, DD1) and a few present variants in the OCRL gene (Dent disease 2, DD2). The aim of the present study was to test the effect on the pre-mRNA splicing process of DD variants, described here or in the literature, and describe the clinical and genotypic features of thirteen unrelated patients with suspected DD. All patients presented tubular proteinuria, ten presented hypercalciuria and five had nephrolithiasis or nephrocalcinosis. CLCN5 and OCRL genes were analyzed by Sanger sequencing. Nine patients showed variants in CLCN5 and four in OCRL; eight of these were new. Bioinformatics tools were used to select fifteen variants with a potential effect on pre-mRNA splicing from our patients' group and from the literature, and were experimentally tested using minigene assays. Results showed that three exonic missense mutations and two intronic variants affect the mRNA splicing process. Our findings widen the genotypic spectrum of DD and provide insight into the impact of variants causing DD.
RESUMO
BACKGROUND: The majority of cases of Dent's disease are caused by pathogenic variants in the CLCN5 gene, which encodes a voltage-gated chloride ion channel (ClC-5), resulting in proximal tubular dysfunction. We present three members of the same family and one unrelated paediatric patient with the same insertion-deletion CLCN5 variant. The identification of these patients and positive familial segregation led to the re-classification of this variant from one of unknown significance to one of likely pathogenicity. CASE PRESENTATION: A 41 year old male presented with end stage kidney failure, proteinuria and haematuria. Whole genome sequencing identified an insertion-deletion variant in CLCN5, resulting in a missense change (c.1744_1745delinsAA p.(Ala582Lys)). His brother and nephew, who both exhibited renal impairment, haematuria, proteinuria, glycosuria and nephrocalcinosis, were found to have the same variant. In addition, genetic testing of an unrelated paediatric patient who presented with proteinuria and hypercalciuria, demonstrated the same variant. CONCLUSIONS: The identification of this novel variant in four individuals with features of Dent's disease, has led to the re-classification of the variant to one of likely pathogenicity. As a result, our patients and any future patients with the same variant can be offered a likely diagnosis, without the need for kidney biopsy, and their family members can be offered genetic screening.
Assuntos
Doença de Dent , Masculino , Humanos , Criança , Adulto , Doença de Dent/diagnóstico , Doença de Dent/genética , Hematúria , Cloretos , Família , ProteinúriaRESUMO
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.
Assuntos
Doença de Dent , Células-Tronco Pluripotentes Induzidas , Masculino , Humanos , Criança , Doença de Dent/complicações , Doença de Dent/genética , Leucócitos Mononucleares , Mutação , Proteinúria/genética , Proteinúria/urinaRESUMO
Dent's disease is a proximal tubulopathy with heterogeneous genetical background. The typical clinical finding is characterized by low molecular weight proteinuria, hypercalciuria, nephrocalcinosis/nephrolithiasis and progressive chronic kidney failure. The underlying cause of the disease is the genetic defect (most commonly CLCN5 mutation) of the receptor-mediated endocytosis in the structure of proximal tubules. The typical fenotype may be composed of extrarenal symptoms. In the event of clinical suspicion, Dent's disease is only verifiable by genetic testing without the necessity of any kidney biopsy. The clinical case can be associated with nephrotic-range proteinuria or kidney failure as an indication of kidney biopsy. The number of articles available at scientific literatures on Dent's disease with the inclusion of renal histology is very slight. According to the pathophysiology of the highlighted Dent's disease and additionally to the expected tubular pathology, global or focal segmental glomerular sclerosis may apply for the majority of cases. Orv Hetil. 2023; 164(20): 788-791.
Assuntos
Doença de Dent , Cálculos Renais , Insuficiência Renal , Humanos , Doença de Dent/complicações , Doença de Dent/diagnóstico , Doença de Dent/genética , Esclerose , Cálculos Renais/genética , Rim , Mutação , ProteinúriaRESUMO
Dent disease is an X-linked recessive renal tubular disorder, which is mainly caused by mutations of the CLCN5 gene and OCRL gene. It is characterized by low molecular weight proteinuria, hypercalciuria, nephrocalcinosis or nephrolithiasis, and progressive renal failure. Nephrotic syndrome is a glomerular disorder characterized by massive proteinuria, hypoalbuminemia, edema, and hyperlipidemia. In this study, we report two cases of Dent disease manifesting as nephrotic syndrome. Two patients were initially diagnosed with nephrotic syndrome due to edema, nephrotic range proteinuria, hypoalbuminemia, and hyperlipidemia, and responded to prednisone and tacrolimus therapy. Genetic testing revealed mutations in the OCRL and CLCN5 genes. They were eventually diagnosed with Dent disease. Nephrotic syndrome is a rare and insidious phenotype of Dent disease, and its pathogenesis is not fully understood. Patients with nephrotic syndrome are recommended to routinely undergo urinary protein classification and urinary calcium testing, especially those with frequently recurrent nephrotic syndrome and poor response to steroid and immunosuppressive therapy. To date, there is no effective drug treatment for Dent disease. About 30% to 80% of patients progress to end-stage renal disease at the age of 30-50.
RESUMO
Dent disease type 1 is suspected in the presence of a complete phenotype of low molecular weight (LMW) proteinuria, hypercalciuria and at least one of the following: nephrocalcinosis, nephrolithiasis, haematuria, hypophosphatemia or chronic kidney disease (CKD). We present two brothers who presented with CKD alone. In the absence of typical clinical features, further assessment of LMW proteinuria and hypercalciuria was not undertaken. Whole-genome sequencing revealed hemizygous loss of function mutations in chloride voltage-gated channel 5 (CLCN5) consistent with Dent disease. Dent disease should, therefore, be considered in patients with an incomplete phenotype, including unexplained CKD alone.
RESUMO
Dent's disease is an X-linked recessive disease characterized by proximal tubulopathy with low-molecular weight proteinuria, hypercalciuria, nephrolithiasis, nephrocalcinosis, and kidney failure. It is mainly caused by mutations in the CLCN5 or OCRL1 genes, and only ~ 250 families have been identified with these mutations. We present a 31-year-old male referred to a nephrology consultation due to elevated serum creatinine and a history of nephrolithiasis. Complementary evaluation revealed protein/creatinine ratio of 1.9 g/g and albumin/creatinine ratio of 0.5 g/g, hypercalciuria and medullary nephrocalcinosis. These findings raised the suspicion of Dent's disease, which was confirmed by genetic testing. A missense mutation in the CLCN5 gene (c.810C>G, p.(Ser270Arg)), not previously reported in populational databases, was identified. During the evaluation of the patient, it came to our attention that a first-degree male cousin was being followed in our kidney transplantation unit. Given the unknown etiology of his chronic kidney disease, genetic testing was performed, identifying the same mutation. This case highlights the importance of considering the diagnosis of Dent's disease in the setting of a male patient with chronic kidney disease of unknown etiology, low-molecular-weight proteinuria, hypercalciuria, and nephrocalcinosis. Despite progression to end-stage kidney failure in a significant portion of male patients, there are no reports of recurrence after kidney transplantation.
RESUMO
INTRODUCTION: Dent's disease is an X-linked inherited renal tubular disorder characterized by proteinuria, hypercalciuria, nephrocalcinosis, nephrolithiasis, rickets, and end-stage renal disease. Almost 60% of patients have causative mutations in the CLCN5 gene (Dent 1), and 15% of affected individuals have mutations in the OCRL1 gene (Dent 2). The aims of this study are to identify CLCN5 mutations in Iranian families with Dent's disease and to characterize the associated clinical syndromes. METHODS: We studied 14 patients from 13 unrelated Iranian families with a clinical diagnosis of Dent's disease. Proteinuria was detected in all patients. Nephrolithiasis was found in 5 patient, and hematuria in 2 patients. Most of the affected individuals had nephrocalcinosis. PCR-sequencing for the CLCN5 gene was performed in all 14 patients. Next-generation sequencing (NGS) has also been performed in one patient who we did not find causative mutation. RESULTS: We identified four different CLCN5 mutations including one missense mutation (c.731C>T), one nonsense mutation (c.100C>T), and two novel mutations, consisting of one frameshift mutation (c.1241_1242dupAA) and one splicing mutation (c.805-2A>G). We also identified one OCRL1 mutation, one splicing mutation (c.1466 + 1G>A), using NGS. CONCLUSION: This is the first report to characterize mutations in the CLCN5 gene in Iranian patients with Dent's disease and expands the spectrum of CLCN5 mutations by reporting two novel mutations, c.1241_1242dupAA and c.805-2A>G.
Assuntos
Doença de Dent , Cálculos Renais , Nefrocalcinose , Humanos , Nefrocalcinose/genética , Irã (Geográfico) , Doença de Dent/diagnóstico , Doença de Dent/genética , Mutação , Proteinúria/genéticaAssuntos
Cálculos Renais , Proteinúria , Criança , Humanos , Proteinúria/diagnóstico , Proteinúria/etiologia , Hipercalciúria , Rim , Biópsia , Canais de Cloreto/genética , MutaçãoRESUMO
BACKGROUND: Dent's disease type 1 (DD1) is a rare X-linked nephropathy caused by CLCN5 mutations, characterized by proximal tubule dysfunction, including low molecular weight proteinuria (LMWP), hypercalciuria, nephrolithiasis-nephrocalcinosis, progressive chronic kidney disease (CKD) and kidney failure (KF). Current management is symptomatic and does not prevent disease progression. Here we describe the contemporary DD1 picture across Europe to highlight its unmet needs. METHODS: A physician-based anonymous international e-survey supported by several European nephrology networks/societies was conducted. Questions focused on DD1 clinical features, diagnostic procedure and mutation spectra. RESULTS: A total of 207 DD1 male patients were reported; clinical data were available for 163 with confirmed CLCN5 mutations. Proteinuria was the most common manifestation (49.1%). During follow-up, all patients showed LMWP, 66.4% nephrocalcinosis, 44.4% hypercalciuria and 26.4% nephrolithiasis. After 5.5 years, ≈50% of patients presented with renal dysfunction, 20.7% developed CKD stage ≥3 and 11.1% developed KF. At the last visit, hypercalciuria was more frequent in paediatric patients than in adults (73.4% versus 19.0%). Conversely, nephrolithiasis, nephrocalcinosis and renal dysfunction were more prominent in adults. Furthermore, CKD progressed with age. Despite no clear phenotype/genotype correlation, decreased glomerular filtration rate was more frequent in subjects with CLCN5 mutations affecting the pore or CBS domains compared with those with early-stop mutations. CONCLUSIONS: Results from this large DD1 cohort confirm previous findings and provide new insights regarding age and genotype impact on CKD progression. Our data strongly support that DD1 should be considered in male patients with CKD, nephrocalcinosis/hypercalciuria and non-nephrotic proteinuria and provide additional support for new research opportunities.
Assuntos
Doença de Dent , Cálculos Renais , Nefrocalcinose , Insuficiência Renal Crônica , Insuficiência Renal , Masculino , Humanos , Nefrocalcinose/etiologia , Nefrocalcinose/genética , Doença de Dent/diagnóstico , Doença de Dent/genética , Hipercalciúria/epidemiologia , Hipercalciúria/genética , Mutação , Europa (Continente)/epidemiologia , Insuficiência Renal Crônica/etiologia , Insuficiência Renal Crônica/genética , Proteinúria/genética , Canais de Cloreto/genéticaRESUMO
BACKGROUND AND OBJECTIVES: Dent's disease type 1 (DD1) is a rare X-linked hereditary pathology caused by CLCN5 mutations that is characterized mainly by proximal tubule dysfunction, hypercalciuria, nephrolithiasis/nephrocalcinosis, progressive chronic kidney disease, and low-weight proteinuria, the molecular hallmark of the disease. Currently, there is no specific curative treatment, only symptomatic and does not prevent the progression of the disease. In this study we have isolated and characterized urinary extracellular vesicles (uEVs) enriched in exosomes that will allow us to identify biomarkers associated with DD1 progression and a better understanding of the pathophysiological bases of the disease. MATERIALS AND METHODS: Through a national call from the Spanish Society of Nephrology (SEN) and the Spanish Society of Pediatric Nephrology (AENP), urine samples were obtained from patients and controls from different Spanish hospitals, which were processed to obtain the uEVS. The data of these patients were provided by the respective nephrologists and/or extracted from the RENALTUBE registry. The uEVs were isolated by ultracentrifugation, morphologically characterized and their protein and microRNA content extracted. RESULTS: 25 patients and 10 controls were recruited, from which the urine was processed to isolate the uEVs. Our results showed that the relative concentration of uEVs/mL is lower in patients compared to controls (0.26 × 106 uEVs/mL vs 1.19 × 106 uEVs/mL, p < 0.01). In addition, the uEVs of the patients were found to be significantly larger than those of the control subjects (mean diameter: 187.8 nm vs 143.6 nm, p < 0.01). Finally, our data demonstrated that RNA had been correctly extracted from both patient and control exosomes. CONCLUSIONS: In this work we describe the isolation and characterization of uEVs from patients with Dent 1 disease and healthy controls, that shall be useful for the subsequent study of differentially expressed cargo molecules in this pathology.
Assuntos
Doença de Dent , Exossomos , MicroRNAs , Nefrocalcinose , Nefrolitíase , Criança , Humanos , Doença de Dent/genética , Doença de Dent/metabolismo , Exossomos/metabolismo , Nefrocalcinose/genéticaRESUMO
Background: Dent disease is a group of inherited X-linked recessive renal tubular disorders. This group of disorders is characterized by low molecular weight proteinuria (LMWP), nephrocalcinosis, hypercalciuria and renal failure. Case presentation: Here we report one 11-year-old Chinese boy (proband) and one 13-year-old Chinese boy who was proband's cousin, both presented with massive proteinuria. Further laboratory examinations revealed a lack of nephrocalcinosis, nor any other signs of tubular dysfunction, but only LMWP and hypercalciuria. There was no abnormality in growth, renal function or mineral density of the bones. A novel deletion (c.1448delG) in the CLCN5 gene was identified, resulting in a frame shift mutation (p.Gly483fs). The proband's and his cousin's mothers were found to be the carrier of this mutation. Conclusions: In this study, we have found a novel frameshift mutation (c. 1448delG) at exon 11 of the CLCN5 gene which leads to Dent disease 1, expanding the spectrum of CLCN5 mutations.
RESUMO
Type 1 Dent disease is caused by changes in chloride voltage-gated channel 5 (CLCN5) gene on chromosome X, which causes the lack or dysfunction of chloride channel ClC-5. Affected subjects show proteinuria and hypercalciuria, and eventually develop end-stage kidney disease. Currently there is no cure for this disease. Here, we used CRISPR-Cas9 technology to develop a Clcn5 mouse model with 95% of the ClC-5 coding region deleted. These mutant mice showed obvious Dent disease-like phenotypes. We used lentiviral vectors to deliver human CLCN5 cDNA into the kidneys of mutant mice by retrograde ureter injection and observed increased megalin expression, improved diuresis, and decreased urinary calcium and protein excretion, which persisted for 3 months. The therapeutic effects diminished 4 months after gene therapy. Our data suggest that immune responses to the transgene products most likely explain the loss of gene therapy effects. This study suggests that gene therapy could be a promising approach to treat Dent disease, but more work is needed to achieve sustained therapeutic effects.
RESUMO
Dent disease is a rare genetic disease characterized by low-molecular-weight proteinuria. Dent disease with Bartter-like syndrome is rare and can easily be misdiagnosed and mistreated. Herein, we report a case of Dent disease 1 with Bartter-like syndrome as the initial manifestation. The patient was admitted to The Second Xiangya Hospital of Central South University due to polydipsia, polyuria, and weakness of both lower limbs at 2 years of age. Laboratory tests showed that serum sodium, potassium and chlorine levels were low, while serum creatinine levels were normal. The calcium level in the urine was normal. The patient was initially diagnosed with Bartter syndrome, and despite medical interventions, he eventually developed chronic kidney disease stage 4 at 13 years of age. To determine the cause, the patient was recommended to undergo genetic testing, which showed a CLCN5 gene c. 941C > T mutation (p.S314L), and was finally diagnosed as Dent disease 1. The clinical manifestations of Dent disease are complex and diverse. For patients with atypical clinical manifestations or unsatisfactory therapeutic effects, genetic testing is recommended.
RESUMO
Mutations in the CLCN5 gene encoding the 2Cl- /1H+ exchanger ClC-5 are associated with Dent disease 1, an inherited renal disorder characterized by low-molecular-weight (LMW) proteinuria and hypercalciuria. In the kidney, ClC-5 is mostly localized in proximal tubule cells, where it is thought to play a key role in the endocytosis of LMW proteins. Here, we investigated the consequences of eight previously reported pathogenic missense mutations of ClC-5 surrounding the "proton glutamate" that serves as a crucial H+ -binding site for the exchanger. A complete loss of function was observed for a group of mutants that were either retained in the endoplasmic reticulum of HEK293T cells or unstainable at plasma membrane due to proteasomal degradation. In contrast, the currents measured for the second group of mutations in Xenopus laevis oocytes were reduced. Molecular dynamics simulations performed on a ClC-5 homology model demonstrated that such mutations might alter ClC-5 protonation by interfering with the water pathway. Analysis of clinical data from patients harboring these mutations demonstrated no phenotype/genotype correlation. This study reveals that mutations clustered in a crucial region of ClC-5 have diverse molecular consequences in patients with Dent disease 1, ranging from altered expression to defects in transport.