Phenotypes Associated with This Genotype

Genotype
MGI:2181788

hm2

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

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

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