Intra-renal and subcellular distribution of the human chloride channel, CLC-5, reveals a pathophysiological basis for Dent's disease

Devuyst, Olivier; Christie, Paul P.T.; Courtoy, Pierre J.; Beauwens, Renaud; Thakker, Rajesh V.

doi:10.1093/hmg/8.2.247

Cited by 257 publications

(275 citation statements)

References 36 publications

Supporting

Mentioning

264

Contrasting

Order By: Relevance

“…Controls included two normal human kidney samples obtained at surgery; two samples from related patients with nephronophthisis as a result of a mutation in NPHP1 and one sample from a patient with FJHN and no detected mutation in UMOD. These samples were routinely fixed in 4% formaldehyde and embedded in paraffin (20). The use of these samples has been approved by the University of Louvain Ethical Review Board.…”

Section: Intrarenal Expression and Urinary Excretion Of Uromodulinmentioning

confidence: 99%

“…A polyclonal sheep antibody (Biodesign International, Saco, ME) and a monoclonal mouse antibody (Cedarlane, Ontario, Canada) against human uromodulin were used (20,21). Other antibodies included a rabbit polyclonal antibody against human aquaporin-1 (AQP1; Chemicon, Temecula, CA), a rabbit polyclonal antibody against the human serotonin receptor 1A (SR1A; Santa Cruz Biotechnology, Santa Cruz, CA) (22), and a rabbit polyclonal antibody against human aquaporin-2 (AQP2; Alamone, Jerusalem, Israel).…”

Section: Intrarenal Expression and Urinary Excretion Of Uromodulinmentioning

confidence: 99%

“…Membrane extracts were prepared as described previously (20). Fresh morning urine samples were also obtained in six FJHN patients with a defined UMOD mutation and various degrees of renal failure (F3-III-1, F3-III-2, F4-IV-1, F6-II-1, F7-II-1, F7-II-2), one patient with renal failure as a result of FJHN without UMOD mutation, six control patients with renal failure related to another nephropathy (reflux nephropathy, n ϭ 2; autosomal dominant polycystic kidney disease, n ϭ 2; chronic glomerulonephritis, n ϭ 2), and two normal subjects.…”

Section: Intrarenal Expression and Urinary Excretion Of Uromodulinmentioning

confidence: 99%

“…The samples were separated by SDS-PAGE and transferred to nitrocellulose (20). After blocking, membranes were incubated overnight at 4°C with primary antibodies, washed, incubated for 1 h at room temperature with appropriate peroxidase-labeled antibodies (Dako, Glostrup, Denmark), washed again, and visualized with enhanced chemiluminescence.…”

Section: Intrarenal Expression and Urinary Excretion Of Uromodulinmentioning

confidence: 99%

See 3 more Smart Citations

A Cluster of Mutations in the UMOD Gene Causes Familial Juvenile Hyperuricemic Nephropathy with Abnormal Expression of Uromodulin

Dahan¹,

Devuyst²,

Smaers³

et al. 2003

Journal of the American Society of Nephrology

199

170

View full text Add to dashboard Cite

Abstract. Familial juvenile hyperuricemic nephropathy (FJHN [MIM 162000]) is an autosomal-dominant disorder characterized by abnormal tubular handling of urate and late development of chronic interstitial nephritis leading to progressive renal failure. A locus for FJHN was previously identified on chromosome 16p12 close to the MCKD2 locus, which is responsible for a variety of autosomal-dominant medullary cystic kidney disease (MCKD2). UMOD, the gene encoding the Tamm-Horsfall/uromodulin protein, maps within the FJHN/MCKD2 critical region. Mutations in UMOD were recently reported in nine families with FJHN/ MCKD2 disease. A mutation in UMOD has been identified in 11 FJHN families (10 missense and one in-frame deletion)-10 of which are novel-clustering in the highly conserved exon 4. The consequences of UMOD mutations on uromodulin expression were investigated in urine samples and renal biopsies from nine patients in four families. There was a markedly increased expression of uromodulin in a cluster of tubule profiles, suggesting an accumulation of the protein in tubular cells. Consistent with this observation, urinary excretion of wild-type uromodulin was significantly decreased. The latter findings were not observed in patients with FJHN without UMOD mutations. In conclusion, this study points to a mutation clustering in exon 4 of UMOD as a major genetic defect in FJHN. Mutations in UMOD may critically affect the function of uromodulin, resulting in abnormal accumulation within tubular cells and reduced urinary excretion.Familial juvenile hyperuricemic nephropathy (FJHN) is an autosomal-dominant disorder characterized by hyperuricemia and decreased urinary excretion of urate, followed by the development of chronic interstitial nephritis most often leading to progressive renal failure (1,2). The link between early hyperuricemia and subsequent progression of renal disease remains unclear.Urate is the end product of purine metabolism in humans, who have lost the expression of the uricase gene during evolution (3). Urate is freely filtered by the glomerulus and essentially reabsorbed, because only 10% of the filtered load is present in the final urine (4). The transport mechanisms of urate are localized in the proximal tubule (PT), whereas no experimental evidence supports urate permeability in the more distal segments of the nephron (5). URAT1, the long-hypothesized apical urate-anion exchanger involved in the reabsorption of urate by PT cells, was recently identified (6). Inactivating mutations of URAT1 located on 11q13 are responsible

show abstract

Section: Intrarenal Expression and Urinary Excretion Of Uromodulinmentioning

confidence: 99%

Section: Intrarenal Expression and Urinary Excretion Of Uromodulinmentioning

confidence: 99%

Section: Intrarenal Expression and Urinary Excretion Of Uromodulinmentioning

confidence: 99%

Section: Intrarenal Expression and Urinary Excretion Of Uromodulinmentioning

confidence: 99%

See 2 more Smart Citations

A Cluster of Mutations in the UMOD Gene Causes Familial Juvenile Hyperuricemic Nephropathy with Abnormal Expression of Uromodulin

Dahan¹,

Devuyst²,

Smaers³

et al. 2003

Journal of the American Society of Nephrology

199

170

View full text Add to dashboard Cite

show abstract

“…ClC-5 was first thought to provide a shunt conductance in early endosomes, enabling efficient intraluminal acidification by V-type H þ ATPase. [4][5][6] It has recently been demonstrated, however, that ClC-5 functions as a Cl À/H þ antiporter when activated by positive voltages. 7,8 No CLCN5 gene mutations are detected in approximately 40% of patients with the classic symptoms of Dent's disease, suggesting a locus heterogeneity.…”

Section: Introductionmentioning

confidence: 99%

An atypical Dent’s disease phenotype caused by co-inheritance of mutations at CLCN5 and OCRL genes

et al. 2012

View full text Add to dashboard Cite

Dent's disease is an X-linked renal tubulopathy caused by mutations mainly affecting the CLCN5 gene. Defects in the OCRL gene, which is usually mutated in patients with Lowe syndrome, have been shown to lead to a Dent-like phenotype called Dent disease 2. However, about 20% of patients with Dent's disease carry no CLCN5/OCRL mutations. The disease's genetic heterogeneity is accompanied by interfamilial and intrafamilial phenotypic heterogeneity. We report on a case of Dent's disease with a very unusual phenotype (dysmorphic features, ocular abnormalities, growth delay, rickets, mild mental retardation) in which a digenic inheritance was discovered. Two different, novel disease-causing mutations were detected, both inherited from the patient's healthy mother, that is a truncating mutation in the CLCN5 gene (A249fs*20) and a donor splice-site alteration in the OCRL gene (c.388 þ 3A4G). The mRNA analysis of the patient's leukocytes revealed an aberrantly spliced OCRL mRNA caused by in-frame exon 6 skipping, leading to a shorter protein, but keeping intact the central inositol 5-phosphatase domain and the C-terminal side of the ASH-RhoGAP domain. Only wild-type mRNA was observed in the mother's leukocytes due to a completely skewed X inactivation. Our results are the first to reveal the effect of an epistatic second modifier in Dent's disease too, which can modulate its expressivity. We surmise that the severe Dent disease 2 phenotype of our patient might be due to an addictive interaction of the mutations at two different genes.

show abstract

Genetic Basis of Renal Stones

Thakker¹

2013

Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism

View full text Add to dashboard Cite

Intra-renal and subcellular distribution of the human chloride channel, CLC-5, reveals a pathophysiological basis for Dent's disease

Cited by 257 publications

References 36 publications

A Cluster of Mutations in the UMOD Gene Causes Familial Juvenile Hyperuricemic Nephropathy with Abnormal Expression of Uromodulin

A Cluster of Mutations in the UMOD Gene Causes Familial Juvenile Hyperuricemic Nephropathy with Abnormal Expression of Uromodulin

An atypical Dent’s disease phenotype caused by co-inheritance of mutations at CLCN5 and OCRL genes

Genetic Basis of Renal Stones

Contact Info

Product

Resources

About