Phenotypes Associated with This Genotype

Genotype
MGI:3510236

• Allelic Composition: Clcn5^tm1Gug/Y
• Genetic Background: involves: 129S1/Sv * 129X1/SvJ * C57BL/6J

• ♀: phenotype observed in females
• ♂: phenotype observed in males
• N: normal phenotype

craniofacial

abnormal tooth development ( J:66560 )

♂ • at 8 weeks, a small number of mutants exhibit backward growth of the teeth

♂ • feeding a liquid diet results in long-term survival but does not improve the teeth or humpback deformities

homeostasis/metabolism

aminoaciduria ( J:66560 )

♂ • hemizygotes show generalized aminoaciduria

♂ • 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)

♂ • in contrast, plasma levels of amino acids remain unaffected relative to wild-type

hydroxyprolinuria ( J:66560 )

♂ • 24-fold increase in urine hydroxyproline level

cystinuria ( J:66560 )

♂ • 22-fold increase in urine cysteine levels

hyperglutaminuria ( J:66560 )

♂ • 11-fold increase in urine glutamine levels

hyperthreoninuria ( J:66560 )

♂ • 10-fold increase in urine threonine levels

increased urine glucose level ( J:66560 )

♂ • hemizygotes exhibit significant glycosuria that is not associated with hyperglycemia

increased urine calcium level ( J:66560 )

♂ • hemizygotes display a 2-fold increase in daily urinary excretion of calcium relative to wild-type

abnormal renal protein reabsorption ( J:66560 , J:84433 )

♂ • 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)

increased urine phosphate level ( J:66560 )

♂

increased urine protein level ( 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)

♂ • specifically, hemizygotes show a 200-fold increase in urinary CC16 excretion relative to wild-type; in contrast, plasma CC16 concentrations remain normal

renal/urinary system

renal/urinary system phenotype ( J:66560 )

♂N • hemizygotes display normal kidney clearance, as assessed by plasma creatinine and creatinine clearance standardized for body weight

aminoaciduria ( J:66560 )

♂ • hemizygotes show generalized aminoaciduria

♂ • 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)

♂ • in contrast, plasma levels of amino acids remain unaffected relative to wild-type

hydroxyprolinuria ( J:66560 )

♂ • 24-fold increase in urine hydroxyproline level

cystinuria ( J:66560 )

♂ • 22-fold increase in urine cysteine levels

hyperglutaminuria ( J:66560 )

♂ • 11-fold increase in urine glutamine levels

hyperthreoninuria ( J:66560 )

♂ • 10-fold increase in urine threonine levels

increased urine glucose level ( J:66560 )

♂ • hemizygotes exhibit significant glycosuria that is not associated with hyperglycemia

increased urine calcium level ( J:66560 )

♂ • hemizygotes display a 2-fold increase in daily urinary excretion of calcium relative to wild-type

abnormal renal protein reabsorption ( J:66560 , J:84433 )

♂ • 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)

increased urine phosphate level ( J:66560 )

♂

increased urine protein level ( J:66560 )

♂ • specifically, hemizygotes show a 200-fold increase in urinary CC16 excretion relative to wild-type; in contrast, plasma CC16 concentrations remain normal

♂ • hemizygotes show a low molecular weight proteinuria that includes vitamin D binding protein (DBP, 50 kDa) and Clara cell protein (CC16, 16 kDa)

abnormal kidney corticomedullary boundary morphology ( J:66560 )

♂ • mutant kidneys exhibit microscopic calcium deposits at the cortico-medullary junction

nephrocalcinosis ( J:66560 )

♂ • mutant kidneys appear histologically normal but exhibit microscopic calcium deposits at the cortico-medullary junction, indicating nephrocalcinosis

polyuria ( 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

skeleton

abnormal tooth development ( J:66560 )

♂ • at 8 weeks, a small number of mutants exhibit backward growth of the teeth

♂ • feeding a liquid diet results in long-term survival but does not improve the teeth or humpback deformities

kyphosis ( J:66560 )

♂ • most mutants are viable at birth and display normal growth and survival to reproductive age

♂ • however, at 8 weeks, ~7% of mutants show hump deformities of the dorsal spine, in the absence of osteopenia or rickets

growth/size/body

abnormal tooth development ( J:66560 )

♂ • at 8 weeks, a small number of mutants exhibit backward growth of the teeth

♂ • feeding a liquid diet results in long-term survival but does not improve the teeth or humpback deformities

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
Dent disease		DOID:0050699	OMIM:300009 OMIM:300555	J:66560