Phenotypes Associated with This Genotype

Genotype
MGI:6467338

• Allelic Composition: Clrn1^tm1.1Ugpa/Clrn1^tm1.1Ugpa; Myo15a^{tm1.1(cre)Ugds}/Myo15a⁺
• Genetic Background: involves: 129S1/SvImJ * C57BL/6N

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

hearing/vestibular/ear

abnormal inner hair cell stereociliary bundle morphology ( J:265318 )

• at >P30, the stereocilia of the short row are heterogeneous in length with some missing entirely in IHCs

• stereocilia progressively regress until hair bundles degenerate completely by P120

• intracochlear AAV2/8-mediated delivery of clarin-1 results in normal hair bundles at P120; however, despite the persistence of V-shaped bundles, stereocilia in the short and middle rows are heterogeneous in length with many found to be missing

abnormal outer hair cell stereociliary bundle morphology ( J:265318 )

• at >P30, the stereocilia of the short row are heterogeneous in length with some missing entirely in OHCs

• stereocilia progressively regress until hair bundles degenerate completely by P120

• intracochlear AAV2/8-mediated delivery of clarin-1 results in normal hair bundles at P120; however, despite the persistence of V-shaped bundles, stereocilia in the short and middle rows are heterogeneous in length with many found to be missing

abnormal cochlear IHC afferent innervation pattern ( J:265318 )

• at P28, TEM analysis revealed enlarged postsynaptic afferent terminals relative to control mice

• at P20, the postsynaptic GluA2/3-immunoreactive domain is abnormally expanded in the nerve terminals below the IHCs

cochlear inner hair cell degeneration ( J:265318 )

• IHC stereociliary bundles degenerate completely by P120

cochlear outer hair cell degeneration ( J:265318 )

• OHC stereociliary bundles degenerate completely by P120

abnormal cochlear inner hair cell physiology ( J:265318 )

• at P18, the Ca²⁺ current density in IHCs is almost twice that in control mice

• analysis of the voltage-dependent activation of Ca²⁺ currents revealed a negative shift of 7 mV at P18-P21 and a significantly less steep activation curve at P18; the negative shift is first noted at P9 prior to any significant changes in current amplitude and density and increases thereafter

• at >P9, the kinetics of Ca²⁺ current activation at negative membrane potentials are slower than in control mice; moreover, time-dependent inactivation of IHC Ca²⁺ currents is greater than in control mice at P13 and P18

increased or absent threshold for auditory brainstem response ( J:265318 )

• at P15-P20, ABR thresholds are 20-40 dB higher than those in control mice at all frequencies tested

• by P30-P60, ABR thresholds reach an SPL of 75-100 dB across the 5- to 40-kHz frequency spectrum

• intracochlear AAV2/8-mediated delivery of clarin-1 leads to a near complete rescue of hearing at all frequencies tested with hearing preserved up to P60

abnormal cochlear nerve compound action potential ( J:265318 )

• at P15-P20, cochlear nerve compound action potential (CAP) wave I latencies recorded in response to loud sound stimuli (SPL of 95 dB) are 30% longer while CAP amplitudes are 75% smaller than in control mice

abnormal cochlear nerve fiber response ( J:265318 )

• at P20, electrically evoked brainstem response (EEBR) waves recorded in the cochleae after direct stimulation of primary auditory neurons are of smaller amplitude than those in control mice and the peaks of waves II (EII) and III (EIII) are significantly delayed

increased or absent distortion product otoacoustic emission threshold ( J:265318 )

• DPOAE thresholds are normal up to P20 but progressively increase to reach an SPL 20-30 dB above that of control mice by P44

deafness ( J:265318 )

• mice exhibit profound deafness at P60

sensorineural hearing loss ( J:265318 )

• mice exhibit progressive hearing loss starting as early as P15 and reaching profound deafness at P60

nervous system

abnormal synaptic vesicle exocytosis ( J:265318 )

• Ca²⁺ efficiency for IHC exocytosis is normal at P9 but significantly lower than that in control mice at P13

• following intracellular Ca²⁺ uncaging by UV flash photolysis, P14 IHCs show lower rates of exocytosis (dC_m/dt) and lower exocytosis maximum amplitudes than control IHCs

abnormal inner hair cell stereociliary bundle morphology ( J:265318 )

• at >P30, the stereocilia of the short row are heterogeneous in length with some missing entirely in IHCs

• stereocilia progressively regress until hair bundles degenerate completely by P120

• intracochlear AAV2/8-mediated delivery of clarin-1 results in normal hair bundles at P120; however, despite the persistence of V-shaped bundles, stereocilia in the short and middle rows are heterogeneous in length with many found to be missing

abnormal outer hair cell stereociliary bundle morphology ( J:265318 )

• at >P30, the stereocilia of the short row are heterogeneous in length with some missing entirely in OHCs

• stereocilia progressively regress until hair bundles degenerate completely by P120

• intracochlear AAV2/8-mediated delivery of clarin-1 results in normal hair bundles at P120; however, despite the persistence of V-shaped bundles, stereocilia in the short and middle rows are heterogeneous in length with many found to be missing

abnormal cochlear IHC afferent innervation pattern ( J:265318 )

• at P28, TEM analysis revealed enlarged postsynaptic afferent terminals relative to control mice

• at P20, the postsynaptic GluA2/3-immunoreactive domain is abnormally expanded in the nerve terminals below the IHCs

cochlear inner hair cell degeneration ( J:265318 )

• IHC stereociliary bundles degenerate completely by P120

cochlear outer hair cell degeneration ( J:265318 )

• OHC stereociliary bundles degenerate completely by P120

abnormal cochlear inner hair cell physiology ( J:265318 )

• at P18, the Ca²⁺ current density in IHCs is almost twice that in control mice

• analysis of the voltage-dependent activation of Ca²⁺ currents revealed a negative shift of 7 mV at P18-P21 and a significantly less steep activation curve at P18; the negative shift is first noted at P9 prior to any significant changes in current amplitude and density and increases thereafter

• at >P9, the kinetics of Ca²⁺ current activation at negative membrane potentials are slower than in control mice; moreover, time-dependent inactivation of IHC Ca²⁺ currents is greater than in control mice at P13 and P18

abnormal cochlear nerve compound action potential ( J:265318 )

• at P15-P20, cochlear nerve compound action potential (CAP) wave I latencies recorded in response to loud sound stimuli (SPL of 95 dB) are 30% longer while CAP amplitudes are 75% smaller than in control mice

abnormal cochlear nerve fiber response ( J:265318 )

• at P20, electrically evoked brainstem response (EEBR) waves recorded in the cochleae after direct stimulation of primary auditory neurons are of smaller amplitude than those in control mice and the peaks of waves II (EII) and III (EIII) are significantly delayed

abnormal synapse morphology ( J:265318 )

• mice exhibit and IHC synaptopathy characterized by a much weaker downregulation of Ca²⁺ currents than normally observed at the onset of hearing; a hyperpolarized voltage-activation curve and an extended calcium-dependent inactivation of Ca²⁺ currents; and an intrinsic defect of the exocytotic machinery

abnormal ribbon synapse morphology ( J:265318 )

• the rate of colocalization for Ca_V1.3- and ribeye-immunoreactive areas is normal at P9, but significantly lower than that in control IHCs at P13 and P21, suggesting a loose spatial coupling between Ca²⁺ channels and the synaptic machinery

• at P13, the F-actin cortical network is disrupted at the IHC ribbon synapse

• however, IHCs exhibit normal frequencies of round (immature) and droplet-shaped (mature) synaptic ribbons at P15 and P28

abnormal cochlear nerve morphology ( J:265318 )

• cochlear immunostaining with Neurofilament 200 (NF200) revealed a significant loss of auditory nerve fibers at P25

cellular

abnormal synaptic vesicle exocytosis ( J:265318 )

• Ca²⁺ efficiency for IHC exocytosis is normal at P9 but significantly lower than that in control mice at P13

• following intracellular Ca²⁺ uncaging by UV flash photolysis, P14 IHCs show lower rates of exocytosis (dC_m/dt) and lower exocytosis maximum amplitudes than control IHCs

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
Usher syndrome type 3A		DOID:0110841	OMIM:276902	J:265318