Mouse Genome Informatics
hm
    Slc12a6tm1Tjj/Slc12a6tm1Tjj
involves: 129/Sv * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
       
hearing/vestibular/ear
• at >1 year, OHCs and IHCs are either both present or both absent in most sections of the organ of Corti
• a few cases where OHCs have degenerated while IHCs are still present are also observed
• the temporal relationship between the degeneration of fibrocytes and hair cells is variable
• at 3 months, 2 of 4 (50%) homozygotes display degeneration of the organ of Corti
• at 5 months or later, 12 of 15 (80%) homozygotes display degeneration of the organ of Corti
• at 5 months or later, homozygotes often show a significant loss of spiral ligament type I fibrocytes
• in contrast, spiral ligament type II fibrocytes are often preserved
• at 5 months or later, homozygotes often show a significant loss of spiral ligament type III fibrocytes
• however, young (<75 days) and old (>110 days) homozygotes show no significant differences in their endocochlear potential or K+ concentration in the scala media relative to age-matched wild-type mice
• old (but not young) homozygotes exhibit a significant decrease in the post-mortem (passive) endocochlear steady-state potential (SSP) relative to wild-type mice
• homozygotes display a slowly progressive hearing loss over the first year of life, as shown by reduced thresholds of auditory brainstem responses to clicks as a function of age

nervous system
• upon exposure to flurothyl, 3-month-old homozygotes show reduced seizure thresholds and increased aberrant electrical activity, including spontaneous high-voltage spike-and-wave-like complexes, on electrocorticograms
• however, no spontaneous seizures are observed
• at P13 (but not at P1), homozygotes exhibit severe degeneration of the cerebellum
• at >1 year, homozygotes display degeneration of the cochlear ganglion, probably secondary to loss of cochlear hair cells
• at P13 (but not at P1), homozygotes display severe degeneration of the sciatic nerve
• at P13 (but not at P1), homozygotes display degeneration of the spinal cord
• analysis of ventral and dorsal roots of the spinal cord indicates that both motor and sensory nerves are affected
• homozygotes exhibit progressive neurodegeneration in the PNS and CNS, esp. in the white matter
• at P13 (but not at P1), homozygotes exhibit severe degeneration of the sciatic nerve, spinal cord, hippocampus, cerebellum, and optic stalk while the corpus callosum remains unaffected
• at >1 year, OHCs and IHCs are either both present or both absent in most sections of the organ of Corti
• a few cases where OHCs have degenerated while IHCs are still present are also observed
• the temporal relationship between the degeneration of fibrocytes and hair cells is variable
• at P13 (but not at P1), homozygotes display severe hippocampal neurodegeneration, esp. in the outer molecular layer of the dentate gyrus along the hippocampal fissure
• vacuolization is more severe at 3 months of age than at P13
• at 3 months, homozygotes exhibit swollen myelinated and unmyelinated axons in their degenerating hippocampi
• degenerating hippocampal unmyelinated axons have synapses that terminate on morphologically intact spines, suggesting that synaptic connections are established prior to degeneration

behavior/neurological
• upon exposure to flurothyl, 3-month-old homozygotes show reduced seizure thresholds and increased aberrant electrical activity, including spontaneous high-voltage spike-and-wave-like complexes, on electrocorticograms
• however, no spontaneous seizures are observed
• when lifted by the tail, 3-week-old homozygotes display abnormal hindlimb grasping instead of the normal extension response
• at >1 year, abnormal forelimb grasping is also observed
• at >1 year, homozygotes sometimes exhibit grossly abnormal positions of their hindlegs while sitting
• at >1 year, homozygotes sometimes lay flat on the ground
• at >1 year, homozygotes are often unable to move their hindlimbs

cardiovascular system
• at 3-5 months, homozygotes exhibit increased arterial hypertension relative to wild-type littermates (118 2 mmHg vs 100 2 mmHg, respectively)
• however, no difference in heart rates are observed

muscle
• at >1 year, homozygotes display an abnormal posture reminiscent of spasticity

vision/eye
• at P13 (but not at P1, homozygotes display degeneration of the optic stalk
• however, no retinal degeneration is observed

cellular
• homozygotes exhibit a severely impaired cell volume regulation, as assessed in proximal renal tubules and hippocampal neurons, and a moderately raised intraneuronal Cl- concentration relative to wild-type mice

skeleton
• at 5 months or later, homozygotes often show a significant loss of spiral ligament type I fibrocytes
• in contrast, spiral ligament type II fibrocytes are often preserved
• at 5 months or later, homozygotes often show a significant loss of spiral ligament type III fibrocytes

Mouse Models of Human Disease
OMIM IDRef(s)
Agenesis of the Corpus Callosum with Peripheral Neuropathy; ACCPN 218000 J:86183