Phenotypes associated with this allele

• Allele Symbol: Clcn3^tm1Lamb
• Allele Name: targeted mutation 1, Fred S Lamb
• Allele ID: MGI:2447864
• Summary: 2 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Clcn3^tm1Lamb/Clcn3^tm1Lamb	involves: 129S1/Sv * 129X1/SvJ	MGI:3720939
hm2	Clcn3^tm1Lamb/Clcn3^tm1Lamb	involves: 129S1/Sv * 129X1/SvJ * C57BL/6J	MGI:3720971

Genotype
MGI:3720939

hm1

• Allelic Composition: Clcn3^tm1Lamb/Clcn3^tm1Lamb
• Genetic Background: involves: 129S1/Sv * 129X1/SvJ

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

mortality/aging

increased susceptibility to induced morbidity/mortality ( J:112692 )

• following surgery to implant a telemetry device to monitor blood pressure and heart rate, 90% of mice die whereas only 6% of wild-type mouse died from the same procedure

• pretreatment with antibiotics (enrofloxacin) reduces mortality following surgery to 50%

immune system

abnormal neutrophil physiology ( J:112692 )

• the maximum velocity of oxygen consumption and reactive oxygen species production in thioglycollate-elicited polymorphonuclear leukocytes (PMNs) treated with opsonized zymosan (OpZ) is decreased relative to in wild-type mice

• oxygen consumption in phorbol myristate acetate-treated PMNs is decreased

• anion selectivity is altered such that preference for chloride ions is equivalent to that for bromide ions whereas PMNs from wild-type mice have a stronger prefernece for chloride ions

impaired neutrophil phagocytosis ( J:112692 )

• polymorphonuclear leukocytes (PMNs) form fewer phagosomes compared to wild-type PMNs

sepsis ( J:112692 )

• following surgery to implant a telemetry device to monitor blood pressure and heart rate, mice develop signs of sepsis including lethargy, shivering, and progressive hypertension followed by death

nervous system

abnormal excitatory postsynaptic currents ( J:122982 )

• the excitatory postsynaptic current is smaller than in wild-type neurons

abnormal excitatory postsynaptic potential ( J:122982 )

• miniature excitatory postsynaptic potential (mEPSP) amplitude declines as a function of chloride ion concentration in contrast to in wild-type neurons

• miniature excitatory postsynaptic potential time constant is attenuated

• mEPSP decay constant is twice as short as in wild-type neurons

• mEPSP amplitude is decreased compared to that in wild-type neurons

• quantal content is decreased relative to that in wild-type neurons

hematopoietic system

abnormal neutrophil physiology ( J:112692 )

• the maximum velocity of oxygen consumption and reactive oxygen species production in thioglycollate-elicited polymorphonuclear leukocytes (PMNs) treated with opsonized zymosan (OpZ) is decreased relative to in wild-type mice

• oxygen consumption in phorbol myristate acetate-treated PMNs is decreased

• anion selectivity is altered such that preference for chloride ions is equivalent to that for bromide ions whereas PMNs from wild-type mice have a stronger prefernece for chloride ions

impaired neutrophil phagocytosis ( J:112692 )

• polymorphonuclear leukocytes (PMNs) form fewer phagosomes compared to wild-type PMNs

cellular

impaired neutrophil phagocytosis ( J:112692 )

• polymorphonuclear leukocytes (PMNs) form fewer phagosomes compared to wild-type PMNs

Genotype
MGI:3720971

hm2

• Allelic Composition: Clcn3^tm1Lamb/Clcn3^tm1Lamb
• Genetic Background: involves: 129S1/Sv * 129X1/SvJ * C57BL/6J

mortality/aging

lethality at weaning, incomplete penetrance ( J:80901 )

• some mice die at weaning

premature death ( J:80901 )

• survival rates are decreased over 10 months

• by 3 months one third of mice are dead and by 6 months half are dead

reproductive system

reduced fertility ( J:80901 )

• matings between female homozygotes and male heterozygotes were unsuccessful with only one litter of pups being born that all died shortly after birth

reduced male fertility ( J:80901 )

♂ • not all males fathered litters

nervous system

abnormal nervous system morphology ( J:80901 )

abnormal brain morphology ( J:80901 )

enlarged lateral ventricles ( J:80901 )

• neuron loss in the hippocampus and entorhinal cortex is accompanied by enlargement of the lateral ventricles and progresses in the same direction as the degeneration (anterior to posterior)

abnormal entorhinal cortex morphology ( J:80901 )

• the entorhinal cortex undergoes a similar degeneration to the one observed in the hippocampus

• by 9 months, neurons are lost from layer 2 and by 1 year neuron loss is occurring in layer 2 and 3

• neuron loss is accompanied by a reduction in entorhinal cortex thickness and exacerbates lateral ventriculomegaly

• gliosis occurs in the entorhinal cortex

• stellate cells from layer 2 and pyramidal cells from layer 3 are lost

abnormal hippocampus morphology ( J:80901 )

• gliosis occurs in the hippocampus

• while neurons are completely lost and replaced by astrocytes, pyramidal cells can still be identified

decreased hippocampus pyramidal cell number ( J:80901 )

• by postnatal day 165, pyramidal cell loss occurs and is more severe in CA3 than in CA1

• by postnatal day 270, pyramidal cell loss is extensive in CA3 and CA1

hippocampal neuron degeneration ( J:80901 )

• neuron loss is evident at postnatal day 73

• neuron loss occurs earlier in the septal (anterior) pole than in the temporal (posterior) pole

• neuron loss is severe among the granule cell of the dentate stratum granulosum

• by postnatal day 270, neurons are replaced with astrocytes and pyramidal cell loss is extensive in CA3 and CA1

• by 12 months all of the neurons in the hippocampus are lost

decreased cerebral cortex pyramidal cell number ( J:80901 )

• pyramidal cells in the entorhinal cortex layer 3 are reduced in number

gliosis ( J:80901 )

• gliosis in the hippocampus is evident at postnatal day 165

• gliosis occurs in the hippocampus and entorhinal cortex

astrocytosis ( J:80901 )

• astrocytosis is evident in the hipposcampus

loss of GABAergic neurons ( J:80901 )

• GABA neurons are specifically lost from the dentate gyrus as detected by GAD67 staining

decreased retina photoreceptor cell number ( J:80901 )

• at postnatal day 23, the number of photoreceptors in the photoreceptor layer is greatly decreased

abnormal nervous system physiology ( J:80901 )

seizures ( J:80901 )

decreased susceptibility to pharmacologically induced seizures ( J:80901 )

• at 4 to 5 weeks of age, only 12.5% of mice experience seizures when treated with pentylenetetrazole compared to 87.5% of wild-type mice

• at 3 to 4 months of age, mice are resistant to pentylenetetrazole-induced seizures but can still be induced to seize with higher doses

• however, response to non-GABAergic seizure inducing agents is the same as in wild-type mice

tonic-clonic seizures ( J:80901 )

• tonic-clonic seizures are observed in 4 mice

behavior/neurological

abnormal behavioral response to xenobiotic ( J:80901 )

• mice have a prolonged recovery time from exposure to benzodiazepines (midazolam) and barbiturates (pentobarbital)

• mice display a reduced time to onset of midazolam-induced immobility and increased duration of immobility with a complete loss of the righting feature observed in wild-type mice

• however, anesthetic response remains normal

enhanced behavioral response to xenobiotic ( J:80901 )

• 20 to 25mg/kg (half the normal dose) is required to induce a surgical plane of anesthesia and often results in death

impaired coordination ( J:80901 )

• when suspended by their tails, 66.7% of mice within 30 seconds and 80% within one minute exhibit an abnormal rear-leg folding behavior

abnormal gait ( J:80901 )

• as early as 2 to 3 weeks, mice have a waddling gait

stereotypic behavior ( J:80901 )

• as early as 2 to 3 weeks, mice are jittery and more excitable than wild-type mice

seizures ( J:80901 )

decreased susceptibility to pharmacologically induced seizures ( J:80901 )

• at 4 to 5 weeks of age, only 12.5% of mice experience seizures when treated with pentylenetetrazole compared to 87.5% of wild-type mice

• at 3 to 4 months of age, mice are resistant to pentylenetetrazole-induced seizures but can still be induced to seize with higher doses

• however, response to non-GABAergic seizure inducing agents is the same as in wild-type mice

tonic-clonic seizures ( J:80901 )

• tonic-clonic seizures are observed in 4 mice

homeostasis/metabolism

decreased circulating glucose level ( J:80901 )

• fasting blood glucose is lower (132+/-7 mg/dl compared to 170+/-13 mg/dl in wild-type mice)

• after being challenged with an intraperitoneal glucose load, peak glucose levels are lower

growth/size/body

decreased body weight ( J:80901 )

• males and females weight less than wild-type mice as early as postnatal day 9 to 11

postnatal growth retardation ( J:80901 )

vision/eye

decreased retina photoreceptor cell number ( J:80901 )

• at postnatal day 23, the number of photoreceptors in the photoreceptor layer is greatly decreased

increased susceptibility to age-related retinal degeneration ( J:80901 )

• postnatal retinal degeneration is rapid and progressive resulting in the complete loss of the photoreceptor layers by postnatal day 23

adipose tissue

abnormal abdominal fat pad morphology ( J:80901 )

• abdominal and other cavity fat pads are absent

skeleton

kyphosis ( J:80901 )

• when sedated, the thoracolumbar and cervicothoracic angles are different than in wild-type mice