Mutations in the CLCN5 gene in Japanese patients with familial idiopathic low-molecular-weight proteinuria

Nakazato, Hitoshi; Hattori, Shinzaburo; Furuse, Akio; Kawano, Tomoyasu; Karashima, Shinnyo; Tsuruta, Motoko; Yoshimuta, Junichiro; Endo, Fumio; Matsuda, Ichiro

doi:10.1038/ki.1997.410

Cited by 43 publications

(29 citation statements)

References 10 publications

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“…This X-linked hypercalciuric stone-forming disorder (Table 1) is due to mutations in the gene that codes for the voltage-gated endosomal chloride channel 5 (CLCN5) (37)(38)(39). Resultant low-molecular-weight proteinuria includes parathyroid hormone (PTH) loss (40,41). As in IH, hypercalciuria results from increased serum calcitriol levels (42), and thiazide treatment lowers urine calcium concentrations (43).…”

Section: Monogenic Disorders That Cause Hypercalciuria and Stonesmentioning

confidence: 99%

Kidney stone disease

Coe

Evan

Worcester

2005

Journal of Clinical Investigation

673

527

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About 5% of American women and 12% of men will develop a kidney stone at some time in their life, and prevalence has been rising in both sexes. Approximately 80% of stones are composed of calcium oxalate (CaOx) and calcium phosphate (CaP); 10% of struvite (magnesium ammonium phosphate produced during infection with bacteria that possess the enzyme urease), 9% of uric acid (UA); and the remaining 1% are composed of cystine or ammonium acid urate or are diagnosed as drug-related stones. Stones ultimately arise because of an unwanted phase change of these substances from liquid to solid state. Here we focus on the mechanisms of pathogenesis involved in CaOx, CaP, UA, and cystine stone formation, including recent developments in our understanding of related changes in human kidney tissue and of underlying genetic causes, in addition to current therapeutics.

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Section: Monogenic Disorders That Cause Hypercalciuria and Stonesmentioning

confidence: 99%

Kidney stone disease

Coe

Evan

Worcester

2005

Journal of Clinical Investigation

673

527

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“…Because of the complex nature of hypercalciuria, encompassing environmental and polygenic factors, the study of individual mechanisms contributing to calciuria has been difficult. Recently, Dent's disease, a monogenic disorder manifesting with hypercalciuria, nephrolithiasis, Fanconi's syndrome, low molecular weight proteinuria, renal insufficiency, and rickets, has been mapped to the gene encoding CLC5, a renal chloride channel of unknown function (1)(2)(3)(4)(5). Expression of mutant CLC5 in Xenopus oocytes results in reduction or abolition of chloride currents compared with wild-type CLC5, suggesting that loss of CLC5 function may play a direct role in the pathogenesis of Dent's disease (3).…”

mentioning

confidence: 99%

Diet-dependent hypercalciuria in transgenic mice with reduced CLC5 chloride channel expression

Luyckx

Leclercq²,

Dowland³

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

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Dent's disease is an X-linked inherited disorder characterized by hypercalciuria, nephrocalcinosis, nephrolithiasis, low molecular weight proteinuria, Fanconi's syndrome, and renal failure. It is caused by inactivating mutations in CLC5, a member of the CLC voltage-gated chloride channel family. CLC5 is known to be expressed in the endosomal compartment of the renal proximal tubule, where it may be required for endosomal acidification and trafficking. Although the Fanconi's syndrome and low molecular weight proteinuria in Dent's disease can be explained by disruption of endosomal function in this nephron segment, the pathogenesis of the hypercalciuria in this disease is unknown. We have generated transgenic mice (RZ) with reduced CLC5 expression by introduction of an antisense ribozyme targeted against CLC5. RZ mice are markedly hypercalciuric compared with nontransgenic control mice, at a time when their serum electrolytes and renal function are otherwise normal. This suggests that hypercalciuria in Dent's disease is a direct consequence of CLC5 hypofunction and is not attributable to a gain of function by mutant CLC5, an effect of modifier genes, or a secondary result of nonspecific renal injury. Surprisingly, hypercalciuria in RZ mice is abolished by dietary calcium deprivation, suggesting that the hypercalciuria may be attributable to gastrointestinal hyperabsorption of calcium rather than a renal calcium leak.

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“…Furthermore, mutations of a renal chloride channel gene, CLCN-5, have been reported in ITP [5, 9, 10]. CLCN-5 abnormalities were identified in patients 1 and 2, but could not be evaluated in patients 3 and 4.…”

Section: Methodsmentioning

confidence: 99%

Poor Renal Accumulation of <sup>99m</sup>Tc-DMSA in Idiopathic Tubular Proteinuria

Suzuki¹,

Suzuki²,

Kume³

et al. 1999

Nephron

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In Japanese patients idiopathic tubular proteinuria presents mainly as asymptomatic tubular low molecular weight proteinuria. This disease has recently been shown to resemble Dent’s disease which is characterized by tubular proteinuria, hypercalciuria, rickets and eventual renal failure. We report on 4 children with idiopathic tubular proteinuria. Although they had normal renal function, as evidenced by serum creatinine or creatinine clearance, they had very poor renal accumulation of ^99mTc-DMSA and the presence of large amounts of tracer in the bladder. Additionally, the patient with the largest amounts of tubular proteinuria had the poorest renal accumulation of the 4 patients. The renal accumulation of tracer decreased with time from a maximum at 10 min after injection. These findings demonstrate that the tracer, once taken to be confined to the proximal tubular cells, is immediately excreted to the tubular lumen. We suggest that poor renal accumulation of ^99mTc-DMSA is very important in elucidating the mechanism of idiopathic tubular proteinuria, and that ^99mTc-DMSA renoscintigraphy is useful in the evaluation of the patient’s renal function over time.

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Mutations in the CLCN5 gene in Japanese patients with familial idiopathic low-molecular-weight proteinuria

Cited by 43 publications

References 10 publications

Kidney stone disease

Kidney stone disease

Diet-dependent hypercalciuria in transgenic mice with reduced CLC5 chloride channel expression

Poor Renal Accumulation of <sup>99m</sup>Tc-DMSA in Idiopathic Tubular Proteinuria

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