Isolated hypercalciuria with mutation in CLCN5: relevance to idiopathic hypercalciuria.
Isolated hypercalciuria with mutation in CLCN5: Relevance to idiopathic hypercalciuria.


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 beta2-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.
Scheinman
S J
SJ
Department of Medicine, SUNY Health Science Center, Syracuse, New York 13210, USA. scheinms@hscsyr.edu
Cox
J P
JP
Lloyd
S E
SE
Pearce
S H
SH
Salenger
P V
PV
Hoopes
R R
RR
Bushinsky
D A
DA
Wrong
O
O
Asplin
J R
JR
Langman
C B
CB
Norden
A G
AG
Thakker
R V
RV
D000293:Adolescent; D000328:Adult; D000818:Animals; D002118:Calcium / Q000652:urine*; D002648:Child; D002675:Child, Preschool; D018118:Chloride Channels / Q000235:genetics*; D005260:Female; D008040:Genetic Linkage; D005820:Genetic Testing; D006801:Humans; D007669:Kidney Calculi / Q000235:genetics / Q000652:urine; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D011507:Proteinuria / Q000235:genetics; D051381:Rats; D014960:X Chromosome
C097503:CLC-5 chloride channel; D018118:Chloride Channels; D002118:Calcium