CLCN5 chloride-channel mutations in six new North American families with X-linked nephrolithiasis

Hoopes, R R; Hueber, Paul; Reid, Robert J.; Braden, Gregory; Goodyer, Paul; Melnyk, Andrew R.; Midgley, Julian; Moel, Donald I.; Neu, Alicia M.; VanWhy, Scott K.; Scheinman, Steven J.

doi:10.1046/j.1523-1755.1998.00061.x

Cited by 57 publications

(48 citation statements)

References 16 publications

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“…All the three nonsense mutations we found were previously reported in other countries [11,19,20,21,22]. The R28stop mutation was previously reported in North America [20] and Japan [19].…”

Section: Discussionsupporting

confidence: 68%

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Truncating Mutations in the Chloride/Proton <i>ClC-5</i> Antiporter Gene in Seven Jewish Israeli Families with Dent’s 1 Disease

Dinour

Davidovitz²,

Levin-Iaina

et al. 2009

Nephron Clin Pract

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Dent’s disease is an X-linked hereditary renal tubular disorder characterized by low-molecular-weight proteinuria (LMWP), hypercalciuria, nephrocalcinosis, nephrolithiasis, rickets and progressive renal failure. About 60% of patients have mutations in the CLCN5 gene (Dent 1), which encodes a kidney-specific chloride/proton antiporter, and 15% of patients have mutations in the OCRL1 gene (Dent 2). The aim of the study was to identify CLCN5 mutations in Jewish Israeli families with Dent‘s disease and to characterize the associated clinical syndromes. We studied 17 patients from 14 unrelated Israeli families with a clinical diagnosis of Dent’s disease. LMWP was detected in all patients. Most of the affected individuals had hypercalciuria and nephrocalcinosis. Renal stones were found in 1 patient, and renal insufficiency developed in 2 patients. We identified six different truncating CLCN5 mutations that were segregated with the disease in 7 families: three nonsense mutations (Arg28stop, Arg467stop and Arg637stop), one deletion mutation (505delA) and two novel mutations, consisted of one deletion mutation (1493delG) and one insertion mutation (409insC). All the mutations cause premature termination of protein translation and result in a non-functional truncated protein. The clinical characteristics of patients with different mutations were, in general, similar.

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“…All the three nonsense mutations we found were previously reported in other countries [11,19,20,21,22]. The R28stop mutation was previously reported in North America [20] and Japan [19].…”

Section: Discussionsupporting

confidence: 68%

“…Hoopes et al [20] described 3 female carriers with symptomatic disease. One of these patients, who was heterozygous for the R28stop mutation, developed symptomatic nephrolithiasis.…”

Section: Discussionmentioning

confidence: 99%

Truncating Mutations in the Chloride/Proton <i>ClC-5</i> Antiporter Gene in Seven Jewish Israeli Families with Dent’s 1 Disease

Dinour

Davidovitz²,

Levin-Iaina

et al. 2009

Nephron Clin Pract

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“…Different types of disease-causing mutations in the CLCN5 gene have been reported (Lloyd et al 1996;Hoopes et al 1998;Morimoto et al 1998;Yamamoto et al 2000;Carballo-Trujillo et al 2003;ClaverieMartin et al 2003;Ludwig et al 2005). Most of these mutations are single nucleotide substitutions that are scattered throughout the coding sequence of the gene.…”

Section: Introductionmentioning

confidence: 99%

A missense mutation in the chloride/proton ClC-5 antiporter gene results in increased expression of an alternative mRNA form that lacks exons 10 and 11. Identification of seven new CLCN5 mutations in patients with Dent’s disease

et al. 2007

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Mutations in the voltage-gated chloride/ proton antiporter ClC-5 gene, CLCN5, are associated with Dent's disease, an X-linked renal tubulopathy. Our interest is to identify and characterize diseasecausing CLCN5 mutations, especially those that alter the splicing of the pre-mRNA. We analyzed the CLCN5 gene from nine unrelated Spanish Dent's disease patients and their relatives by DNA sequencing. Pre-mRNA splicing analysis was performed by RT-PCR. Seven new mutations were identified, consisting of three missense mutations (C219R, F273L, and W547G), one splice-site mutation (IVS-2A > G), one deletion (976delG), and two non-sense mutations (Y140X and W314X). We found that missense mutation W547G also led to increased expression of a new alternative isoform lacking exons 10 and 11 that was expressed in several human tissues. In addition, we describe another novel CLCN5 splicing variant lacking exon 11 alone, which was expressed only in human skeletal muscle. We conclude that missense mutation W547G can also alter the expression levels of a CLCN5 mRNA splicing variant. This type of mutation has not been previously described in the CLCN5 gene. Our results support the importance of a routine analysis at the pre-mRNA level of mutations that are commonly assumed to cause single amino acids alterations.

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“…It is associated with mutations that inactivate the voltage-gated chloride channel ClC-5 (1)(2)(3)(4)(5). This channel is expressed in intracellular membranes of the cortical proximal tubule, medullary thick ascending limb, and ␣-intercalated cells of the human nephron (6).…”

mentioning

confidence: 99%

Responsiveness of Hypercalciuria to Thiazide in Dent’s Disease

Raja¹,

Schurman²,

D’Mello³

et al. 2002

Journal of the American Society of Nephrology

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Abstract. Hypercalciuria is the major risk factor promoting stone formation in Dent's disease, also known as X-linked recessive nephrolithiasis, but the effects of diuretics on calcium excretion and other stone risk factors in this disease are unknown. This study examined urine composition in eight male patients with Dent's disease, ages 6 to 49 yr, all of whom were hypercalciuric and had inactivating mutations of CLCN5. Eight males, ages 7 to 34 yr, with idiopathic hypercalciuria (IH) served as controls. Patients were instructed to maintain a consistent intake of sodium, potassium, calcium, and protein.Two consecutive 24-h urine collections were obtained after a baseline period and after 2 wk of chlorthalidone (25 mg), amiloride (5 mg), and the two diuretics in combination, with a week off drug separating the treatment periods in a randomized crossover design. Doses were reduced by half in boys under age 12 yr. Chlorthalidone alone (P Ͻ 0.002) and the combination of chlorthalidone and amiloride (P Ͻ 0.003) reduced calcium excretion significantly in either patient group. With chlorthalidone, calcium excretion fell to normal (Ͻ4.0 mg/kg per d) in all but one patient in each group. Amiloride alone had no significant effect on urinary calcium excretion, in either patient group. In patients with Dent's disease during chlorthalidone therapy, the supersaturation ratios for calcium oxalate and calcium phosphate fell by 25% and 35%, respectively. Mean citrate excretion was reduced by chlorthalidone (P Ͻ .04) and by chlorthalidone in combination with amiloride (P Ͻ .02). There were no significant differences in the responses to these diuretics between the patient groups in any of the urinary parameters. The intact hypocalciuric response to a thiazide diuretic indicates that inactivation of the ClC-5 chloride channel does not impair calcium transport in the distal convoluted tubule and indicates that thiazides should be useful in reducing the risk of kidney stone recurrence in patients with Dent's disease.

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CLCN5 chloride-channel mutations in six new North American families with X-linked nephrolithiasis

Abstract: These studies expand the range of mutations identified in this disease, and broaden the phenotypic range to include clinically affected women and the first North American case with severe rickets.

Cited by 57 publications

References 16 publications

Truncating Mutations in the Chloride/Proton <i>ClC-5</i> Antiporter Gene in Seven Jewish Israeli Families with Dent’s 1 Disease

Truncating Mutations in the Chloride/Proton <i>ClC-5</i> Antiporter Gene in Seven Jewish Israeli Families with Dent’s 1 Disease

A missense mutation in the chloride/proton ClC-5 antiporter gene results in increased expression of an alternative mRNA form that lacks exons 10 and 11. Identification of seven new CLCN5 mutations in patients with Dent’s disease

Responsiveness of Hypercalciuria to Thiazide in Dent’s Disease

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