Mouse Genome Informatics
ot
    Clcn5tm1Gug/Y
involves: 129S1/Sv * 129X1/SvJ * C57BL/6J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
       
craniofacial
• at 8 weeks, a small number of mutants exhibit backward growth of the teeth (J:66560)
• feeding a liquid diet results in long-term survival but does not improve the teeth or humpback deformities (J:66560)

homeostasis/metabolism
• hemizygotes show generalized aminoaciduria (J:66560)
• hyperaminoaciduria is more pronounced for neutral and polar amino acids, e.g. citrulline (94-fold increase, hydroxyproline (24-fold increase), cysteine (22-fold increase), glutamine (11-fold increase) and threonine (10-fold increase) (J:66560)
• in contrast, plasma levels of amino acids remain unaffected relative to wild-type (J:66560)
• hemizygotes exhibit significant glycosuria that is not associated with hyperglycemia (J:66560)
• hemizygotes display a severe impairment of protein endocytosis by the kidney proximal tubule cells (PTCs) (J:66560)
• analytical subcellular fractionation and quantitative immunogold labeling revealed that impaired apical protein endocytosis is due to a trafficking defect of megalin and cubilin in PTCs (J:84433)
• failure of apical endocytosis ocucrs in the absence of ultrastructural changes in PTCs or deficits in rate-limiting endocytic catalysts (J:84433)
• hemizygotes display a 2-fold increase in daily urinary excretion of calcium relative to wild-type (J:66560)
• hemizygotes show a low molecular weight proteinuria that includes vitamin D binding protein (DBP, 50 kDa) and Clara cell protein (CC16, 16 kDa) (J:66560)
• specifically, hemizygotes show a 200-fold increase in urinary CC16 excretion relative to wild-type; in contrast, plasma CC16 concentrations remain normal (J:66560)

renal/urinary system
N
• hemizygotes display normal kidney clearance, as assessed by plasma creatinine and creatinine clearance standardized for body weight (J:66560)
• hemizygotes show generalized aminoaciduria (J:66560)
• hyperaminoaciduria is more pronounced for neutral and polar amino acids, e.g. citrulline (94-fold increase, hydroxyproline (24-fold increase), cysteine (22-fold increase), glutamine (11-fold increase) and threonine (10-fold increase) (J:66560)
• in contrast, plasma levels of amino acids remain unaffected relative to wild-type (J:66560)
• hemizygotes exhibit significant glycosuria that is not associated with hyperglycemia (J:66560)
• hemizygotes display a severe impairment of protein endocytosis by the kidney proximal tubule cells (PTCs) (J:66560)
• analytical subcellular fractionation and quantitative immunogold labeling revealed that impaired apical protein endocytosis is due to a trafficking defect of megalin and cubilin in PTCs (J:84433)
• failure of apical endocytosis ocucrs in the absence of ultrastructural changes in PTCs or deficits in rate-limiting endocytic catalysts (J:84433)
• hemizygotes display a 2-fold increase in daily urinary excretion of calcium relative to wild-type (J:66560)
• hemizygotes show a low molecular weight proteinuria that includes vitamin D binding protein (DBP, 50 kDa) and Clara cell protein (CC16, 16 kDa) (J:66560)
• specifically, hemizygotes show a 200-fold increase in urinary CC16 excretion relative to wild-type; in contrast, plasma CC16 concentrations remain normal (J:66560)
• mutant kidneys exhibit microscopic calcium deposits at the cortico-medullary junction (J:66560)
• mutant kidneys appear histologically normal but exhibit microscopic calcium deposits at the cortico-medullary junction, indicating nephrocalcinosis (J:66560)
• in some hemizygotes, the polyuria, which correlates with glycosuria, results in a daily diuresis that is 50% greater than that in wild-type littermates and is equivalent to 30% of body weight (J:66560)

skeleton
• most mutants are viable at birth and display normal growth and survival to reproductive age (J:66560)
• however, at 8 weeks, ~7% of mutants show hump deformities of the dorsal spine, in the absence of osteopenia or rickets (J:66560)

growth/size
• at 8 weeks, a small number of mutants exhibit backward growth of the teeth (J:66560)
• feeding a liquid diet results in long-term survival but does not improve the teeth or humpback deformities (J:66560)

Mouse Models of Human Disease
OMIM IDRef(s)
Dent Disease 1 300009 J:66560