Isolated hypercalciuria with mutation in CLCN5: Relevance to idiopathic hypercalciuria

Steven J. Scheinman; Jeremy P D Cox; Sarah E. Lloyd; Simon H S Pearce; Page V. Salenger; Richard R. Hoopes; David A. Bushinsky; Oliver Wrong; John R. Asplin; Craig B. Langman; Anthony G W Norden; Rajesh V. Thakker

doi:10.1046/j.1523-1755.2000.00774.x

Isolated hypercalciuria with mutation in CLCN5: Relevance to idiopathic hypercalciuria

Steven J. Scheinman^*, Jeremy P D Cox, Sarah E. Lloyd, Simon H S Pearce, Page V. Salenger, Richard R. Hoopes, David A. Bushinsky, Oliver Wrong, John R. Asplin, Craig B. Langman, Anthony G W Norden, Rajesh V. Thakker

^*Corresponding author for this work

Pediatrics

Research output: Contribution to journal › Article › peer-review

68 Scopus citations

Abstract

Background. Idiopathic hypercalciuria (IH) is the most common risk factor for kidney stones and often has a genetic component. Dent's disease (X-linked nephrolithiasis) is associated with mutations in the CLCN5 chloride channel gene, and low molecular weight (LMW) proteinuria was universally observed in affected males. We sought to identify mutations in CLCN5 or abnormalities in LMW protein excretion in a large group of patients with IH and in a rat model of genetic hypercalciuria. Methods. One hundred and seven patients with IH (82 adults and 25 children) and one asymptomatic hypercalciuric man with a known inactivating mutation in CLCN5 were studied. Secondary causes of hypercalciuria were excluded in all. The excretion of retinol-binding protein and β2-microglobulin was measured by immunoassay in 101 patients with IH. Mutation analysis of the CLCN5 gene was performed in 32 patients with IH and in the genetic hypercalciuric stone-forming (GHS) rat strain. Results. LMW protein excretion was normal in 92 patients with IH, and only slight abnormalities were found in the other nine, none of whom had a mutation in CLCN5. One 27-year-old man who had a CLCN5 mutation was found to have isolated hypercalciuria without LMW proteinuria, renal failure, or other evidence of renal disease. Mutation analysis was normal in 32 patients with IH. The CLCN5 sequence was normal in the GHS rat. Conclusions. Inactivation of CLCN5 can be found in the setting of hypercalciuria without other features of X-linked nephrolithiasis. However, mutations in CLCN5 do not represent a common cause of IH.

Original language	English (US)
Pages (from-to)	232-239
Number of pages	8
Journal	Kidney international
Volume	57
Issue number	1
DOIs	https://doi.org/10.1046/j.1523-1755.2000.00774.x
State	Published - 2000

Funding

This work was supported by the National Institutes of Health: DK46838 (S.J. Scheinman and R.R Hoopes) and DK47631 (D.A. Bushinsky and J. Asplin); the North Atlantic Treaty Organization CGR950114 (S.J. Scheinman and R.V. Thakker); the Medical Research Council (UK) (S.E. Lloyd, S.H.S. Pearce, J. Cox, and R.V. Thakker); a McNulty Foundation grant to the Bone and Mineral Metabolism Fund (C.B. Langman); and the Sir Jules Thorn Charitable Trust (A. Norden). S.H.S. Pearce and J.P.D. Cox were MRC Clinical Training Fellows. Preliminary reports of these observations were presented at the American Society of Nephrology annual meeting in 1995 (abstracts; J Am Soc Nephrol 6:954, 1995, and 6:727, 1995).

Keywords

Chloride channel
Dent's disease
Kidney stones
Low molecular weight proteinuria
X-linked nephrolithiasis

ASJC Scopus subject areas

Nephrology

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Scheinman, S. J., Cox, J. P. D., Lloyd, S. E., Pearce, S. H. S., Salenger, P. V., Hoopes, R. R., Bushinsky, D. A., Wrong, O., Asplin, J. R., Langman, C. B., Norden, A. G. W., & Thakker, R. V. (2000). Isolated hypercalciuria with mutation in CLCN5: Relevance to idiopathic hypercalciuria. Kidney international, 57(1), 232-239. https://doi.org/10.1046/j.1523-1755.2000.00774.x

@article{5e94e6fb4fba40158f68cd230e8d6bd3,

title = "Isolated hypercalciuria with mutation in CLCN5: Relevance to idiopathic hypercalciuria",

abstract = "Background. Idiopathic hypercalciuria (IH) is the most common risk factor for kidney stones and often has a genetic component. Dent's disease (X-linked nephrolithiasis) is associated with mutations in the CLCN5 chloride channel gene, and low molecular weight (LMW) proteinuria was universally observed in affected males. We sought to identify mutations in CLCN5 or abnormalities in LMW protein excretion in a large group of patients with IH and in a rat model of genetic hypercalciuria. Methods. One hundred and seven patients with IH (82 adults and 25 children) and one asymptomatic hypercalciuric man with a known inactivating mutation in CLCN5 were studied. Secondary causes of hypercalciuria were excluded in all. The excretion of retinol-binding protein and β2-microglobulin was measured by immunoassay in 101 patients with IH. Mutation analysis of the CLCN5 gene was performed in 32 patients with IH and in the genetic hypercalciuric stone-forming (GHS) rat strain. Results. LMW protein excretion was normal in 92 patients with IH, and only slight abnormalities were found in the other nine, none of whom had a mutation in CLCN5. One 27-year-old man who had a CLCN5 mutation was found to have isolated hypercalciuria without LMW proteinuria, renal failure, or other evidence of renal disease. Mutation analysis was normal in 32 patients with IH. The CLCN5 sequence was normal in the GHS rat. Conclusions. Inactivation of CLCN5 can be found in the setting of hypercalciuria without other features of X-linked nephrolithiasis. However, mutations in CLCN5 do not represent a common cause of IH.",

keywords = "Chloride channel, Dent's disease, Kidney stones, Low molecular weight proteinuria, X-linked nephrolithiasis",

author = "Scheinman, {Steven J.} and Cox, {Jeremy P D} and Lloyd, {Sarah E.} and Pearce, {Simon H S} and Salenger, {Page V.} and Hoopes, {Richard R.} and Bushinsky, {David A.} and Oliver Wrong and Asplin, {John R.} and Langman, {Craig B.} and Norden, {Anthony G W} and Thakker, {Rajesh V.}",

note = "Funding Information: This work was supported by the National Institutes of Health: DK46838 (S.J. Scheinman and R.R Hoopes) and DK47631 (D.A. Bushinsky and J. Asplin); the North Atlantic Treaty Organization CGR950114 (S.J. Scheinman and R.V. Thakker); the Medical Research Council (UK) (S.E. Lloyd, S.H.S. Pearce, J. Cox, and R.V. Thakker); a McNulty Foundation grant to the Bone and Mineral Metabolism Fund (C.B. Langman); and the Sir Jules Thorn Charitable Trust (A. Norden). S.H.S. Pearce and J.P.D. Cox were MRC Clinical Training Fellows. Preliminary reports of these observations were presented at the American Society of Nephrology annual meeting in 1995 (abstracts; J Am Soc Nephrol 6:954, 1995, and 6:727, 1995).",

year = "2000",

doi = "10.1046/j.1523-1755.2000.00774.x",

language = "English (US)",

volume = "57",

pages = "232--239",

journal = "Kidney international",

issn = "0085-2538",

publisher = "Nature Publishing Group",

number = "1",

}

TY - JOUR

T1 - Isolated hypercalciuria with mutation in CLCN5

T2 - Relevance to idiopathic hypercalciuria

AU - Scheinman, Steven J.

AU - Cox, Jeremy P D

AU - Lloyd, Sarah E.

AU - Pearce, Simon H S

AU - Salenger, Page V.

AU - Hoopes, Richard R.

AU - Bushinsky, David A.

AU - Wrong, Oliver

AU - Asplin, John R.

AU - Langman, Craig B.

AU - Norden, Anthony G W

AU - Thakker, Rajesh V.

N1 - Funding Information: This work was supported by the National Institutes of Health: DK46838 (S.J. Scheinman and R.R Hoopes) and DK47631 (D.A. Bushinsky and J. Asplin); the North Atlantic Treaty Organization CGR950114 (S.J. Scheinman and R.V. Thakker); the Medical Research Council (UK) (S.E. Lloyd, S.H.S. Pearce, J. Cox, and R.V. Thakker); a McNulty Foundation grant to the Bone and Mineral Metabolism Fund (C.B. Langman); and the Sir Jules Thorn Charitable Trust (A. Norden). S.H.S. Pearce and J.P.D. Cox were MRC Clinical Training Fellows. Preliminary reports of these observations were presented at the American Society of Nephrology annual meeting in 1995 (abstracts; J Am Soc Nephrol 6:954, 1995, and 6:727, 1995).

PY - 2000

Y1 - 2000

N2 - Background. Idiopathic hypercalciuria (IH) is the most common risk factor for kidney stones and often has a genetic component. Dent's disease (X-linked nephrolithiasis) is associated with mutations in the CLCN5 chloride channel gene, and low molecular weight (LMW) proteinuria was universally observed in affected males. We sought to identify mutations in CLCN5 or abnormalities in LMW protein excretion in a large group of patients with IH and in a rat model of genetic hypercalciuria. Methods. One hundred and seven patients with IH (82 adults and 25 children) and one asymptomatic hypercalciuric man with a known inactivating mutation in CLCN5 were studied. Secondary causes of hypercalciuria were excluded in all. The excretion of retinol-binding protein and β2-microglobulin was measured by immunoassay in 101 patients with IH. Mutation analysis of the CLCN5 gene was performed in 32 patients with IH and in the genetic hypercalciuric stone-forming (GHS) rat strain. Results. LMW protein excretion was normal in 92 patients with IH, and only slight abnormalities were found in the other nine, none of whom had a mutation in CLCN5. One 27-year-old man who had a CLCN5 mutation was found to have isolated hypercalciuria without LMW proteinuria, renal failure, or other evidence of renal disease. Mutation analysis was normal in 32 patients with IH. The CLCN5 sequence was normal in the GHS rat. Conclusions. Inactivation of CLCN5 can be found in the setting of hypercalciuria without other features of X-linked nephrolithiasis. However, mutations in CLCN5 do not represent a common cause of IH.

AB - Background. Idiopathic hypercalciuria (IH) is the most common risk factor for kidney stones and often has a genetic component. Dent's disease (X-linked nephrolithiasis) is associated with mutations in the CLCN5 chloride channel gene, and low molecular weight (LMW) proteinuria was universally observed in affected males. We sought to identify mutations in CLCN5 or abnormalities in LMW protein excretion in a large group of patients with IH and in a rat model of genetic hypercalciuria. Methods. One hundred and seven patients with IH (82 adults and 25 children) and one asymptomatic hypercalciuric man with a known inactivating mutation in CLCN5 were studied. Secondary causes of hypercalciuria were excluded in all. The excretion of retinol-binding protein and β2-microglobulin was measured by immunoassay in 101 patients with IH. Mutation analysis of the CLCN5 gene was performed in 32 patients with IH and in the genetic hypercalciuric stone-forming (GHS) rat strain. Results. LMW protein excretion was normal in 92 patients with IH, and only slight abnormalities were found in the other nine, none of whom had a mutation in CLCN5. One 27-year-old man who had a CLCN5 mutation was found to have isolated hypercalciuria without LMW proteinuria, renal failure, or other evidence of renal disease. Mutation analysis was normal in 32 patients with IH. The CLCN5 sequence was normal in the GHS rat. Conclusions. Inactivation of CLCN5 can be found in the setting of hypercalciuria without other features of X-linked nephrolithiasis. However, mutations in CLCN5 do not represent a common cause of IH.

KW - Chloride channel

KW - Dent's disease

KW - Kidney stones

KW - Low molecular weight proteinuria

KW - X-linked nephrolithiasis

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UR - http://www.scopus.com/inward/citedby.url?scp=0034001447&partnerID=8YFLogxK

U2 - 10.1046/j.1523-1755.2000.00774.x

DO - 10.1046/j.1523-1755.2000.00774.x

M3 - Article

C2 - 10620204

AN - SCOPUS:0034001447

SN - 0085-2538

VL - 57

SP - 232

EP - 239

JO - Kidney international

JF - Kidney international

IS - 1

ER -

Isolated hypercalciuria with mutation in CLCN5: Relevance to idiopathic hypercalciuria

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