INT164753

Context Info Confidence 0.58 First Reported 2010 Last Reported 2010 Negated 0 Speculated 0 Reported most in Body Documents 2 Total Number 7 Disease Relevance 5.13 Pain Relevance 0.20

endosome (Clcn5) transport (Clcn5) Golgi apparatus (Clcn5) plasma membrane (Clcn5) transmembrane transport (Clcn5)

Anatomy Link Frequency duct 1 tubule 1 kidney 1 urine 1 Clcn5 (Mus musculus)

Pain Link Frequency Relevance Heat imagery 3 91.72 anesthesia 1 83.44 Glutamate 6 63.40 Sicca syndrome 6 5.00 fibrosis 6 5.00 Pain 6 5.00 medulla 6 5.00 abdominal pain 6 5.00

Disease Link Frequency Relevance Heat Targeted Disruption 20 99.96 Hyperthyroidism 6 99.16 Disease 300 97.36 Kidney Stones 246 96.60 Nephrocalcinosis 84 95.84 Sprains And Strains 18 87.48 Dent Disease 114 85.60 Congenital Anomalies 18 84.72 Familial Hypophosphatemia 12 83.20 Proteinuria 96 82.44

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Key:

Protein

Mutation

Event

Anatomy

Negation

Speculation

Pain term

Disease term

Studies in mice have demonstrated that inactivation of ClC-5 is associated with a severe trafficking defect in PT cells, with loss of megalin and cubilin at the brush border, subsequent loss of their ligands in the urine, and impaired lysosomal processing [22,23,27].

Negative_regulation (inactivation) of ClC-5 in urine

1) Confidence 0.58 Published 2010 Journal Orphanet J Rare Dis Section Body Doc Link PMC2964617 Disease Relevance 0.68 Pain Relevance 0.03

Furthermore, genetic inactivation of the Clcn5 gene in mice mimics the severe PT dysfunction observed in Dent's disease, including hypercalciuria and nephrocalcinosis (see below).

Negative_regulation (inactivation) of Clcn5 associated with kidney stones, disease and nephrocalcinosis

2) Confidence 0.43 Published 2010 Journal Orphanet J Rare Dis Section Body Doc Link PMC2964617 Disease Relevance 0.66 Pain Relevance 0

For instance, it has been suggested that collecting duct cells lacking ClC-5 may show an impaired ability of internalization of calcium crystals adhering to apical cell surface [35].

Negative_regulation (lacking) of ClC-5 in duct

3) Confidence 0.43 Published 2010 Journal Orphanet J Rare Dis Section Body Doc Link PMC2964617 Disease Relevance 1.02 Pain Relevance 0

The hypercalciuria observed in patients with Dent's disease and some ClC-5-deficient mice may be secondary to the PT dysfunction (urinary loss of vitamin D binding protein and reduced phosphate absorption, leading to increased 1,25(OH)2-vitamin D3 synthesis) or, at least in part, caused by the functional loss of ClC-5 in the TAL.

Negative_regulation (loss) of ClC-5 associated with disease and kidney stones

4) Confidence 0.43 Published 2010 Journal Orphanet J Rare Dis Section Body Doc Link PMC2964617 Disease Relevance 0.98 Pain Relevance 0

In summary, we can hypothesize that the functional loss of ClC-5 is essentially reflected by manifestations of PT dysfunction and may contribute to the genesis of kidney stones in different ways, reflecting its involvement in specific tubular functions.

Negative_regulation (loss) of ClC-5 in kidney associated with kidney stones

5) Confidence 0.43 Published 2010 Journal Orphanet J Rare Dis Section Body Doc Link PMC2964617 Disease Relevance 0.90 Pain Relevance 0

Mice lacking ClC-5 develop a euthyroid goiter, which results from impaired apical iodide efflux (secondary to down-regulated pendrin) rather than defective apical endocytosis [37].

Negative_regulation (lacking) of ClC-5 associated with hyperthyroidism

6) Confidence 0.43 Published 2010 Journal Orphanet J Rare Dis Section Body Doc Link PMC2964617 Disease Relevance 0.67 Pain Relevance 0

The cortical uptake of (99m)Tc-DMSA was abolished in Clcn5 knockout mice, a model of proximal tubule dysfunction.

Negative_regulation (abolished) of Clcn5 in tubule associated with targeted disruption

7) Confidence 0.37 Published 2010 Journal Am. J. Physiol. Renal Physiol. Section Abstract Doc Link 19955188 Disease Relevance 0.23 Pain Relevance 0.17

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