ORPHA: 1652, 93622; DO: 0111815;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| Xp11.23 | Proteinuria, low molecular weight, with hypercalciuric nephrocalcinosis | 308990 | X-linked recessive | 3 | CLCN5 | 300008 |
A number sign (#) is used with this entry because of evidence that low molecular weight proteinuria with hypercalciura and nephrocalcinosis is caused by mutation in the chloride channel-5 gene (CLCN5; 300008) on chromosome Xp11.
Low molecular weight proteinuria with hypercalciuria and nephrocalcinosis is a form of X-linked hypercalciuric nephrocalcinosis, a group of disorders characterized by proximal renal tubular reabsorptive failure, hypercalciuria, nephrocalcinosis, and renal insufficiency. These disorders have also been referred to as the 'Dent disease complex' (Scheinman, 1998; Gambaro et al., 2004). For a general discussion of Dent disease, see 300009.
Suzuki et al. (1985) identified 5 boys with asymptomatic proteinuria in a screening program of Japanese children. More than 50% of their urinary proteins were those with a molecular weight of less than 40 kD, defined by Suzuki et al. (1985) as low molecular weight (LMW) proteins, including lysozyme (153450) and beta-2-microglobulin (109700). Serum proteins with a molecular weight of less than 50 kD are freely filtered by the renal glomeruli, but the filtered proteins in normal persons are then almost completely reabsorbed at the proximal tubules. Thus, the patients appeared to have an impaired proximal tubular reabsorption of LMW proteins. Follow-up for 4 to 16 years found that 3 patients developed further evidence of tubular dysfunction, including glycosuria, hypophosphatemia, aminoaciduria, and increasing serum creatinine, indicating that it was a progressive disorder. In urine specimens from the patients reported by Suzuki et al. (1985), Murakami et al. (1987) also detected alpha-1-acid glycoprotein (orosomucoid; 138600), alpha-1-microglobulin (176870), and retinol-binding protein (180250), all of which have low molecular weights.
Murakami and Kawakami (1990) reported a slight tendency toward shortening stature with increasing age in affected children. Renal biopsies showed focal changes, including focal glomerulosclerosis and focal tubular atrophy, in approximately one-third of patients.
In studying first-degree relatives of 8 male patients with asymptomatic LMW proteinuria in 6 families, Kawakami et al. (1991) found elevated urinary levels of beta-2-microglobulin in 2 of 6 fathers and 2 of 6 mothers and in 4 of 12 other first-degree relatives. The authors concluded that the increased frequency in fathers argued against X-linked inheritance.
Geary et al. (1985) described 3 patients in England, 2 boys and a girl, with possible asymptomatic LMW proteinuria, indicating that the disorder was not confined to Japan.
Furuse et al. (1992) described 6 male patients with what they referred to as familial progressive renal tubulopathy but recognized as identical to familial low molecular weight proteinuria. The 6 patients belonged to 2 families in a single kindred: the propositus, his father, a paternal first cousin, 2 paternal uncles, and a maternal uncle. X-linked inheritance was thought to be most likely, but the possibility of autosomal dominant inheritance remained because of the occurrence of abnormality on both sides of the family. Furuse et al. (1992) suggested that the disorder may be progressive since older subjects showed more severe tubular dysfunction. All 6 had aminoaciduria and hypercalciuria, whereas glycosuria was present in 2 and phosphaturia in 4.
Igarashi et al. (1995) found that patients with low molecular weight proteinuria tended to have hypercalciuric nephrocalcinosis without rickets or renal failure. Some children additionally demonstrated hematuria, glycosuria, amino aciduria, impaired urinary concentrating ability, and a mild decrease in creatinine clearance.
In affected members of 4 unrelated Japanese kindreds with LMW proteinuria, Lloyd et al. (1997) identified 4 different mutations in the CLCN5 gene (300008.0001 and 300008.0008-300008.0010).
Nakazato et al. (1997) identified mutations in the CLCN5 gene in affected members of 2 Japanese families with low molecular weight proteinuria.
Akuta et al. (1997) identified mutations in the CLCN5 gene in 7 of 10 unrelated Japanese patients with low molecular weight proteinuria, hypercalciuria, and nephrocalcinosis. They estimated that over 70% of Japanese patients with the disorder have mutations in the CLCN5 gene.
Akuta, N., Lloyd, S. E., Igarashi, T., Shiraga, H., Matsuyama, T., Yokoro, S., Cox, J. P. D., Thakker, R. V. Mutations of CLCN5 in Japanese children with idiopathic low molecular weight proteinuria, hypercalciuria and nephrocalcinosis. Kidney Int. 52: 911-916, 1997. [PubMed: 9328929] [Full Text: https://doi.org/10.1038/ki.1997.412]
Furuse, A., Futagoishi, Y., Karashima, S., Hattori, S., Matsuda, I. Familial progressive renal tubulopathy. Clin. Nephrol. 37: 192-197, 1992. [PubMed: 1582058]
Gambaro, G., Vezzoli, G., Casari, G., Rampoldi, L., D'Angelo, A., Borghi, L. Genetics of hypercalciuria and calcium nephrolithiasis: from the rare monogenic to the common polygenic forms. Am. J. Kidney Dis. 44: 963-986, 2004. [PubMed: 15558518] [Full Text: https://doi.org/10.1053/j.ajkd.2004.06.030]
Geary, D. F., Dillon, M. J., Gammon, K., Barratt, T. M. Tubular proteinuria in children without other defects of renal function. Nephron 40: 329-331, 1985. [PubMed: 4010847] [Full Text: https://doi.org/10.1159/000183487]
Igarashi, T., Hayakawa, H., Shiraga, H., Kawato, H., Yan, K., Kawaguchi, H., Yamanake, T., Tsuchida, S., Akagi, K. Hypercalciuria and nephrocalcinosis in patients with idiopathic low molecular weight proteinuria in Japan: is the disease identical to Dent's disease in the United Kingdom? Nephron. 69: 242-247, 1995. [PubMed: 7753256] [Full Text: https://doi.org/10.1159/000188464]
Kawakami, H., Murakami, T., Matsuyama, S. Frequency of elevated urinary beta-2-microglobulin levels in relatives of patients with asymptomatic low molecular weight proteinuria. Pediat. Nephrol. 5: 277-278, 1991. [PubMed: 1867978] [Full Text: https://doi.org/10.1007/BF00867474]
Lloyd, S. E., Pearce, S. H. S., Gunther, W., Kawaguchi, H., Igarashi, T., Jentsch, T. J., Thakker, R. V. Idiopathic low molecular weight proteinuria associated with hypercalciuric nephrocalcinosis in Japanese children is due to mutations of the renal chloride channel (CLCN5). J. Clin. Invest. 99: 967-974, 1997. [PubMed: 9062355] [Full Text: https://doi.org/10.1172/JCI119262]
Murakami, T., Kawakami, H., Matsuyama, S., Terashima, T., Karashima, S., Hattori, S. Asymptomatic low molecular weight proteinuria: studies in five patients. Clin. Nephrol. 28: 93-98, 1987. [PubMed: 3308234]
Murakami, T., Kawakami, H. The clinical significance of asymptomatic low molecular weight proteinuria detected on routine screening of children in Japan: a survey of 53 patients. Clin. Nephrol. 33: 12-19, 1990. [PubMed: 1689232]
Nakazato, H., Hattori, S., Furuse, A., Kawano, T., Karashima, S., Tsuruta, M., Yoshimuta, J., Endo, F., Matsuda, I. Mutations in the CLCN5 gene in Japanese patients with familial idiopathic low-molecular-weight proteinuria. Kidney Int. 52: 895-900, 1997. [PubMed: 9328927] [Full Text: https://doi.org/10.1038/ki.1997.410]
Scheinman, S. J. X-linked hypercalciuric nephrolithiasis: clinical syndromes and chloride channel mutations. Kidney Int. 53: 3-17, 1998. [PubMed: 9452994] [Full Text: https://doi.org/10.1046/j.1523-1755.1998.00718.x]
Suzuki, Y., Okada, T., Higuchi, A., Mase, D., Kobayashi, O. Asymptomatic low molecular weight proteinuria: a report on 5 cases. Clin. Nephrol. 23: 249-254, 1985. [PubMed: 4006335]