Phenotypes associated with this allele

• Allele Symbol: Cacna1d^tm1Jst
• Allele Name: targeted mutation 1, Jorg Striessnig
• Allele ID: MGI:2180141
• Summary: 3 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Cacna1d^tm1Jst/Cacna1d^tm1Jst	B6.129S7-Cacna1d^tm1Jst	MGI:3697360
hm2	Cacna1d^tm1Jst/Cacna1d^tm1Jst	involves: 129S7/SvEvBrd * C57BL/6J	MGI:2181788
cx3	Cacna1d^tm1Jst/Cacna1d^tm1Jst Kcnj5^tm1Clph/Kcnj5^tm1Clph	involves: 129S7/SvEvBrd * 129X1/SvJ * C57BL/6J	MGI:5823281

Genotype
MGI:3697360

hm1

• Allelic Composition: Cacna1d^tm1Jst/Cacna1d^tm1Jst
• Genetic Background: B6.129S7-Cacna1d^tm1Jst

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

hearing/vestibular/ear

abnormal cochlear IHC afferent innervation pattern ( J:88205 , J:108908 , J:113161 )

• at P7, myelin figures typical of cellular degeneration are ultrastructurally found in some afferent nerve endings at the base of IHCs in the apical turns while basal turns show no degenerative changes (J:108908)

• at P15, IHCs show progressive degeneration of afferent nerve fibers (J:108908)

• at P15, afferent nerve fibres are devoid of cytoplasmatic components (mitochondria, vesicles and ribosomes) and contain numerous myelin figures (J:108908)

• in contrast, at P15, efferent nerve endings do not show any ultrastructural changes in membranes or organelles in the cytosol, have a high density of vesicles and typical subsurface cisternae (J:108908)

• by P35, nearly all afferent nerve endings have disappeared (J:108908)

• starting at ~2 months (P55-P65), homozygotes show a progressive reduction in the number of type I SGN dendrites projecting to IHCs, with only ~4 afferent dendrite fibers per IHC at P200 vs ~10 in wild-type mice (J:113161)

abnormal cochlear IHC efferent innervation pattern ( J:88205 , J:108908 , J:113161 )

• strikingly, mutant IHCs show continued presence of efferent cholinergic synaptic transmission up to 4 weeks after birth, whereas cholinergic innervation of wild-type IHCs is lost at the onset of hearing (J:88205)

• in contrast to afferent fibers, no changes in efferent fiber morphology are noted between P7 and P15 (J:108908)

• at P15, as afferent nerve fibers progressively degenerate, efferent nerve fibers appear to form direct synaptic contacts with IHCs (J:108908)

• abnormal axosomatic efferent contacts are noted within both apical and basal turns until P15 (J:108908)

• by P35, nearly all efferent nerve endings have disappeared (J:108908)

• homozygotes exhibit prolonged persistence of efferent IHC synapses, as shown by continued presence of axosomatic synapses in mutant IHCs even at P30, though at a lower number (J:113161)

abnormal inner hair cell synaptic ribbon morphology ( J:113161 )

• starting at ~2 months (P55-P65), homozygotes show a progressive reduction in the number of ribbon-containing synapses of IHCs, with only ~3 ribbons per IHC at P200 vs ~10 in wild-type mice

• however, no obvious differences in the abundance of other key synaptic proteins are noted at 3 weeks of age

absent active-zone-anchored inner hair cell synaptic ribbon ( J:108908 )

• at P3-P15, synaptic bodies are rarely observed at the base of IHCs

• however, synaptic bodies are readily detectable in younger homozygotes (P1 to P3)

cochlear hair cell degeneration ( J:108908 )

• cochlear OHCs appear to degenerate sooner than IHCs, with a discrete pattern of OHC degeneration first noted at P15 mainly in the apical turns

• by 8 months, nearly all sensory cells of the organ of Corti are lost

cochlear inner hair cell degeneration ( J:85915 , J:108908 , J:113161 )

• at or before P3, homozygotes display IHCs in all turns of the cochlea, with no ultrastructural changes in the afferent nerve endings at the basal pole of IHCs (J:108908)

• at P7, myelin figures typical of cellular degeneration are ultrastructurally found in some afferent nerve endings at the base of IHCs in the apical turns while basal turns show no degenerative changes (J:108908)

• until P15, IHCs display a normal ultrastructure of biomembranes, organelles and cilias (J:108908)

• at P35, some remaining IHCs are detectable at the light microscopic level; however, by 8 months, nearly all IHCs are lost in all cochlear turns (J:108908)

• a partial IHC degeneration is observed at ~5 months of age (J:113161)

cochlear outer hair cell degeneration ( J:108908 )

• at or before P3, homozygotes display OHCs in all turns of the cochlea

• at P15, homozygotes show a sporadic loss of OHCs in the apical turn whereas all OHCs are present in the basal turn

• at P35, only a few OHCs are detectable at the light microscopic level; however, by 8 months, nearly all OHCs are lost in all cochlear turns

abnormal cochlear inner hair cell physiology ( J:88205 , J:113161 )

• at 3 weeks, mutant IHCs show a ~92% reduction of the Ca²⁺ current, with a similar reduction in depolarization-induced exocytic increases of membrane capacitance (Cm) relative to wild-type IHCs (J:88205)

• Ca²⁺ current density and exocytosis of mutant IHCs are reduced to ~5-10% of wild-type values both at P16 and P14-P32 (J:88205)

• residual Ca²⁺ current density displays a developmental decrease during the second postnatal week, and fails to support postnatal Ca²⁺ spiking at P7 (J:88205)

• at 3 weeks, 60% of the residual Ca²⁺ current is mediated by L-type Ca²⁺ channels, as it is sensitive to dihydropyridines but resistant to inhibitors of non-L-type Ca²⁺ channels (J:88205)

• mutant IHCs lack functional large-conductance Ca²⁺-activated K⁺ (BK) channels up to 4 weeks after birth (J:88205)

• in contrast, mechanoelectrical transduction currents and K⁺ currents mediated by K_V and KCNQ channels are present (J:88205)

• mutant IHCs display prolonged persistence of efferent cholinergic synapses and reduced abundance of KCNMA1 mRNA, probably due to lack of afferent synaptic activity and neonatal Ca²⁺ action potential firing (J:113161)

deafness ( J:108908 )

sensorineural hearing loss ( J:108908 )

behavior/neurological

behavior/neurological phenotype ( J:85915 )

N • at 6 months, homozygotes show normal motor function, including beam balance, motor co-ordination, motor reflexes, and spontaneous locomotor activity

N • at 6 months, homozygotes display normal nociceptive responses to noxious thermal (hot-plate) and mechanical stimuli (von Frey and tail pressure test)

absent pinna reflex ( J:85915 , J:108908 )

• at 6 months, homozygotes show absence of ear twitch responses to acoustic alarm signals (J:85915)

• homozygotes lack a typical motor reflex initiated by a sudden auditory stimulus at all ages (J:108908)

nervous system

nervous system phenotype ( J:85915 )

N • homozygotes show normal hippocampal synaptic plasticity, with no significant differences in NMDA receptor-dependent and NMDA receptor-independent long-term potentiation in the CA1 region relative to wild-type mice

abnormal cochlear IHC afferent innervation pattern ( J:88205 , J:108908 , J:113161 )

• at P7, myelin figures typical of cellular degeneration are ultrastructurally found in some afferent nerve endings at the base of IHCs in the apical turns while basal turns show no degenerative changes (J:108908)

• at P15, IHCs show progressive degeneration of afferent nerve fibers (J:108908)

• at P15, afferent nerve fibres are devoid of cytoplasmatic components (mitochondria, vesicles and ribosomes) and contain numerous myelin figures (J:108908)

• in contrast, at P15, efferent nerve endings do not show any ultrastructural changes in membranes or organelles in the cytosol, have a high density of vesicles and typical subsurface cisternae (J:108908)

• by P35, nearly all afferent nerve endings have disappeared (J:108908)

• starting at ~2 months (P55-P65), homozygotes show a progressive reduction in the number of type I SGN dendrites projecting to IHCs, with only ~4 afferent dendrite fibers per IHC at P200 vs ~10 in wild-type mice (J:113161)

abnormal cochlear IHC efferent innervation pattern ( J:88205 , J:108908 , J:113161 )

• strikingly, mutant IHCs show continued presence of efferent cholinergic synaptic transmission up to 4 weeks after birth, whereas cholinergic innervation of wild-type IHCs is lost at the onset of hearing (J:88205)

• in contrast to afferent fibers, no changes in efferent fiber morphology are noted between P7 and P15 (J:108908)

• at P15, as afferent nerve fibers progressively degenerate, efferent nerve fibers appear to form direct synaptic contacts with IHCs (J:108908)

• abnormal axosomatic efferent contacts are noted within both apical and basal turns until P15 (J:108908)

• by P35, nearly all efferent nerve endings have disappeared (J:108908)

• homozygotes exhibit prolonged persistence of efferent IHC synapses, as shown by continued presence of axosomatic synapses in mutant IHCs even at P30, though at a lower number (J:113161)

abnormal inner hair cell synaptic ribbon morphology ( J:113161 )

• starting at ~2 months (P55-P65), homozygotes show a progressive reduction in the number of ribbon-containing synapses of IHCs, with only ~3 ribbons per IHC at P200 vs ~10 in wild-type mice

• however, no obvious differences in the abundance of other key synaptic proteins are noted at 3 weeks of age

absent active-zone-anchored inner hair cell synaptic ribbon ( J:108908 )

• at P3-P15, synaptic bodies are rarely observed at the base of IHCs

• however, synaptic bodies are readily detectable in younger homozygotes (P1 to P3)

cochlear hair cell degeneration ( J:108908 )

• cochlear OHCs appear to degenerate sooner than IHCs, with a discrete pattern of OHC degeneration first noted at P15 mainly in the apical turns

• by 8 months, nearly all sensory cells of the organ of Corti are lost

cochlear inner hair cell degeneration ( J:85915 , J:108908 , J:113161 )

• at or before P3, homozygotes display IHCs in all turns of the cochlea, with no ultrastructural changes in the afferent nerve endings at the basal pole of IHCs (J:108908)

• at P7, myelin figures typical of cellular degeneration are ultrastructurally found in some afferent nerve endings at the base of IHCs in the apical turns while basal turns show no degenerative changes (J:108908)

• until P15, IHCs display a normal ultrastructure of biomembranes, organelles and cilias (J:108908)

• at P35, some remaining IHCs are detectable at the light microscopic level; however, by 8 months, nearly all IHCs are lost in all cochlear turns (J:108908)

• a partial IHC degeneration is observed at ~5 months of age (J:113161)

cochlear outer hair cell degeneration ( J:108908 )

• at or before P3, homozygotes display OHCs in all turns of the cochlea

• at P15, homozygotes show a sporadic loss of OHCs in the apical turn whereas all OHCs are present in the basal turn

• at P35, only a few OHCs are detectable at the light microscopic level; however, by 8 months, nearly all OHCs are lost in all cochlear turns

abnormal cochlear inner hair cell physiology ( J:88205 , J:113161 )

• at 3 weeks, mutant IHCs show a ~92% reduction of the Ca²⁺ current, with a similar reduction in depolarization-induced exocytic increases of membrane capacitance (Cm) relative to wild-type IHCs (J:88205)

• Ca²⁺ current density and exocytosis of mutant IHCs are reduced to ~5-10% of wild-type values both at P16 and P14-P32 (J:88205)

• residual Ca²⁺ current density displays a developmental decrease during the second postnatal week, and fails to support postnatal Ca²⁺ spiking at P7 (J:88205)

• at 3 weeks, 60% of the residual Ca²⁺ current is mediated by L-type Ca²⁺ channels, as it is sensitive to dihydropyridines but resistant to inhibitors of non-L-type Ca²⁺ channels (J:88205)

• mutant IHCs lack functional large-conductance Ca²⁺-activated K⁺ (BK) channels up to 4 weeks after birth (J:88205)

• in contrast, mechanoelectrical transduction currents and K⁺ currents mediated by K_V and KCNQ channels are present (J:88205)

• mutant IHCs display prolonged persistence of efferent cholinergic synapses and reduced abundance of KCNMA1 mRNA, probably due to lack of afferent synaptic activity and neonatal Ca²⁺ action potential firing (J:113161)

cochlear ganglion degeneration ( J:108908 , J:113161 )

• at P15, homozygotes exhibit significant degeneration of spiral ganglion cells in the apical region at the ultrastructural level (J:108908)

• at P15, some nerve fibers are detached from the adjacent myelin layers with myelin figures within fibers (J:108908)

• at P15, abnormal gaps along regions of contact between spiral ganglion and Schwann cells are observed (J:108908)

• at P35, spiral ganglion cells are noticeably degenerated in both the apical and basal turns, as evidenced by myelin distortion and myelin figures (J:108908)

• by 8 months, the number of ganglion cells is further reduced, all nerve fibers in the osseous spiral lamina are lost, and myelin figures reflect a pathological transformation with irregular cleavage of myelin lamellae (J:108908)

• homozygotes show a comparable afferent dendrite and spiral ganglion cell loss (reduction to ~50%) within ~8 weeks after birth (J:113161)

abnormal cochlear nerve morphology ( J:85915 )

• homozygotes exhibit degeneration of the auditory nerve

• however, no detectable loss of neurons is observed in the hippocampus CA1 region, dentate gyrus, primary visual cortex VA1, or cerebellar cortex

• in addition, no evidence for degenerative processes in other afferent neurons of the auditory system (e.g. nuclei cochleares, corpus trapezoideum, lemniscus lateralis, nuclei olivae, auditory cortex) is observed

homeostasis/metabolism

homeostasis/metabolism phenotype ( J:85915 )

N • at 6 months, homozygotes display no differences in rectal temperature relative to wild-type mice

growth/size/body

decreased body weight ( J:85915 )

• at 6 months, homozygotes display a significantly lower body weight relative to wild-type mice, despite similar levels of food and water intake

Genotype
MGI:2181788

hm2

• Allelic Composition: Cacna1d^tm1Jst/Cacna1d^tm1Jst
• Genetic Background: involves: 129S7/SvEvBrd * C57BL/6J

mortality/aging

mortality/aging ( J:63515 )

N • homozygous mutant pups obtained from heterozygous crossings are slightly underrepresented at birth (15% vs expected 25%); however, no decrease in the number of pups is observed in homozygous crossings

hearing/vestibular/ear

cochlear inner hair cell degeneration ( J:63515 )

• by P35, homozygotes display complete IHC degeneration

• however, no morphological IHC changes are noted up to P14

cochlear outer hair cell degeneration ( J:63515 , J:117764 )

• at P14, homozygotes display an early and severe OHC degeneration starting on the apical side (J:63515)

• OHC degeneration is complete by P35 (J:63515)

• at P15, severe loss of OHCs occurs exclusively in low frequency (LF; apical/medial) cochlear turns, whereas high frequency (HF; midbasal/basal) OHCs remain histologically intact (J:117764)

abnormal cochlear inner hair cell physiology ( J:63515 , J:117764 )

• at P9, mutant cochlear IHCs display a >90% reduction in voltage-gated L-type Ca²⁺ currents, leading to a nearly complete loss of Ca²⁺ influx which normally couples sound-evoked depolarization to neurotransmitter release at the IHC synapse (J:63515)

• at P22, mutant IHCs show complete absence of expression of the BK channel in all cochlear turns (both LF and HF) (J:117764)

abnormal cochlear outer hair cell physiology ( J:117764 )

• prior to OHC degeneration, homozygotes show complete absence of expression of the Ca²⁺-activated large conductance K⁺ (BK) channel in LF apical/medial turns

• in contrast, OHCs in the remaining HF (midbasal/basal) turns display regular expression of the BK channel at P22

• despite deafness, young (1-mo-old) homozygotes display mechanically intact OHCs in HF (midbasal/basal) cochlear turns, as shown by functional DPOAEs

increased or absent threshold for auditory brainstem response ( J:63515 , J:117764 )

• as early as P14, all homozygotes exhibit increased auditory thresholds (>120 db SPL) relative to age-matched wild-type mice (50-60 db SPL) (J:63515)

• at 5-8 weeks, mutant auditory thresholds are >120 dB SPL relative to wild-type thresholds (30-40 db SPL) (J:63515)

abnormal distortion product otoacoustic emission ( J:117764 )

• at P30, growth functions of DPOAEs are reduced in amplitude but significantly above noise level beyond 40 dB SPL f1, indicating active cochlear mechanics at moderate to high stimulus frequencies despite deafness

• however, at >2 months, growth functions are significantly reduced and no longer differ from the noise floor level, indicating a decline in cochlear mechanics

deafness ( J:63515 , J:117764 )

• all homozygotes are congenitally deaf, as shown by complete absence of typical click-evoked auditory brainstem response (ABR) waveforms above 30 dB SPL at P14 (J:63515)

sensorineural hearing loss ( J:63515 )

cardiovascular system

abnormal heart rate ( J:230439 )

• hearts are susceptible to atrial tachyarrhythmias

• injection of the A1 adenosine receptor (A1R)-selective agonist 2-chloro, N6-cyclopentyl adenosine (CCPA) during A1R-induced bradycardia strongly slows heart rate similarly to wild-type mice and induces deep SAN bradycardia and very low heart rate

abnormal sinus arrhythmia ( J:63515 )

• unlike wild-type mice, homozygotes exhibit severe arrhythmia, as shown by a high standard deviation of R-R intervals at rest

• arrhythmia is reduced during enhanced spontaneous physical activity, and abolished after block of cardiac muscarinic receptors by atropine

increased heart rate variability ( J:230439 )

• mice show high variability of heart rate variability (supraventricular arrhythmia)

• the IKACh (Kcnj5) peptide blocker tertiapin-Q improves heart rate

decreased heart rate ( J:63515 )

• unlike wild-type mice, homozygotes exhibit severe bradycardia, as shown by an increased mean R-R interval at rest

• bradycardia is reduced during enhanced spontaneous physical activity, and abolished after block of cardiac muscarinic receptors by atropine

• however, bradycardia persists after methoxamine treatment, as R-R intervals are increased in both mutant and wild-type mice to similar extents

prolonged RR interval ( J:63515 )

• unlike wild-type mice, homozygotes display an increased mean R-R interval and a high standard deviation of R-R intervals at rest

• however, QRS complexes are triggered by normal P waves and are of normal duration

sinus bradycardia ( J:230439 )

• mice exhibit sinoatrial node (SAN) bradycardia

increased heart rate ( J:230439 )

• mice exhibit atrial tachycardia after intracardiac atrial stimulation

atrial fibrillation ( J:230439 )

• mice exhibit atrial fibrillation after intracardiac atrial stimulation

abnormal sinoatrial node conduction ( J:63515 , J:230439 )

• ECG recordings at rest indicate altered sinoatrial node pacemaker activity (bradycardia and arrhythmia) (J:63515)

• sinoatrial node dysfunction is confirmed in completely denervated, spontaneously beating isolated atria, where mutants display a significant bradycardia and/or arrhythmia relative to wild-type mice (J:63515)

• however, myocardial architecture, myocyte shape and size, and sinoatrial node architecture is normal, and normal pacemaker activity can be reestablished after atropine treatment (J:63515)

• sinoatrial node pauses (J:230439)

• treatment with atropine and propranolol abolishes SAN pauses (J:230439)

• treatment with atropine to block muscarinic receptors reduces the frequency of SAN pauses (J:230439)

• the IKACh (Kcnj5) peptide blocker tertiapin-Q rescues SAN dysfunction (J:230439)

heart block ( J:230439 )

• severe atrioventricular dysfunction typical of congenital heart block

atrioventricular block ( J:63515 , J:230439 )

• unlike wild-type mice, 7 of 11 homozygotes exhibit episodes of second-degree AV block (J:63515)

• frequent episodes of atrioventricular (AV) block (J:230439)

• treatment with atropine and propranolol abolishes AV blocks (J:230439)

• the IKACh (Kcnj5) peptide blocker tertiapin-Q rescues AV block (J:230439)

prolonged PR interval ( J:63515 , J:230439 )

• homozygotes exhibit a prolonged PR interval relative to wild-type mice (543 ms vs 432 ms, respectively) (J:63515)

• prolonged atrioventricular conduction time (PR interval) (J:230439)

• the PR interval of hearts is more than doubled by acetycholine perfusion (J:230439)

abnormal myocardial fiber physiology ( J:230439 )

• acetylcholine decreases pacemaker activity of myocytes by increasing the incidence of delayed after-depolarizations, leaving unaffected the slope of the diastolic depolarization rather than by reducing the slop of the diastolic depolarization and by increasing the frequency of delayed after-depolarizations as in wild-type mice

• slower frequency of spontaneous intracellular calcium transients in sinoatrial node myocytes

behavior/neurological

absent pinna reflex ( J:63515 )

• all homozygotes fail to exhibit a Preyer reflex in response to hand claps

nervous system

cochlear inner hair cell degeneration ( J:63515 )

• by P35, homozygotes display complete IHC degeneration

• however, no morphological IHC changes are noted up to P14

cochlear outer hair cell degeneration ( J:63515 , J:117764 )

• at P14, homozygotes display an early and severe OHC degeneration starting on the apical side (J:63515)

• OHC degeneration is complete by P35 (J:63515)

• at P15, severe loss of OHCs occurs exclusively in low frequency (LF; apical/medial) cochlear turns, whereas high frequency (HF; midbasal/basal) OHCs remain histologically intact (J:117764)

abnormal cochlear inner hair cell physiology ( J:63515 , J:117764 )

• at P9, mutant cochlear IHCs display a >90% reduction in voltage-gated L-type Ca²⁺ currents, leading to a nearly complete loss of Ca²⁺ influx which normally couples sound-evoked depolarization to neurotransmitter release at the IHC synapse (J:63515)

• at P22, mutant IHCs show complete absence of expression of the BK channel in all cochlear turns (both LF and HF) (J:117764)

abnormal cochlear outer hair cell physiology ( J:117764 )

• prior to OHC degeneration, homozygotes show complete absence of expression of the Ca²⁺-activated large conductance K⁺ (BK) channel in LF apical/medial turns

• in contrast, OHCs in the remaining HF (midbasal/basal) turns display regular expression of the BK channel at P22

• despite deafness, young (1-mo-old) homozygotes display mechanically intact OHCs in HF (midbasal/basal) cochlear turns, as shown by functional DPOAEs

cochlear ganglion degeneration ( J:63515 )

• by P35, homozygotes show complete degeneration of the afferent nerve fibers and ganglion cells

• however, no morphological ganglion cell changes are noted up to P14

abnormal action potential ( J:230439 )

• atrial myocytes exhibit shortened action potential duration

homeostasis/metabolism

homeostasis/metabolism phenotype ( J:63515 )

N • homozygotes display no significant differences in plasma norepinephrine or thyroid hormone (free T3 or T4) concentrations relative to wild-type mice

N • also, homozygotes show no differences in serum glucose and insulin levels during fasting or after glucose challenge relative to wild-type mice

abnormal calcium ion homeostasis ( J:63515 )

• at P9, mutant cochlear IHCs display a >90% reduction in voltage-gated L-type Ca²⁺ currents, leading to a nearly complete loss of Ca²⁺ influx which normally couples sound-evoked depolarization to neurotransmitter release at the IHC synapse

• in contrast, no gross abnormalities are noted in vestibular function or structure up to P35

Genotype
MGI:5823281

cx3

• Allelic Composition: Cacna1d^tm1Jst/Cacna1d^tm1Jst; Kcnj5^tm1Clph/Kcnj5^tm1Clph
• Genetic Background: involves: 129S7/SvEvBrd * 129X1/SvJ * C57BL/6J

cardiovascular system

cardiovascular system phenotype ( J:230439 )

N • mice exhibit amelioration of sinoatrial node dysfunction, prevention of tachycardia-bradycardia syndrome, and normalization of atrioventricular (AV) impulse conduction when compared to single Cacna1d homozygotes indicating rescue of sick sinus syndrome and heart block

N • the IKACh (Kcnj5) peptide blocker tertiapin-Q does not affect heart rate

N • no atrial fibrillation or atrial tachycardia is seen after intracardiac atrial stimulation and atrial myocytes show normal action potential duration