Phenotypes associated with this allele

• Allele Symbol: Kcnma1^tm1Ruth
• Allele Name: targeted mutation 1, P Ruth
• Allele ID: MGI:3050114
• Summary: 4 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Kcnma1^tm1Ruth/Kcnma1^tm1Ruth	129-Kcnma1^tm1Ruth	MGI:3711314
hm2	Kcnma1^tm1Ruth/Kcnma1^tm1Ruth	involves: 129/Sv * C57BL/6	MGI:3050200
hm3	Kcnma1^tm1Ruth/Kcnma1^tm1Ruth	involves: 129X1/SvJ	MGI:3629389
cn4	Kcnma1^tm1Ruth/Kcnma1^tm2.1Ruth X/Tg(Myh11-icre/ERT2)1Soff	involves: 129/Sv * C57BL/6 * FVB/N	MGI:3845037

Genotype
MGI:3711314

hm1

• Allelic Composition: Kcnma1^tm1Ruth/Kcnma1^tm1Ruth
• Genetic Background: 129-Kcnma1^tm1Ruth

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

hearing/vestibular/ear

abnormal cochlear IHC afferent innervation pattern ( J:109217 )

• mutant IHCs show a reduced number of low (<5 sp/s) spontaneous rate auditory nerve (AN) fibers relative to wild-type (4% vs 18%, respectively), consistent with a slight IHC depolarization in mutant ears

abnormal cochlear inner hair cell physiology ( J:109217 )

• apical IHCs isolated from P22- to P30-old homozygotes selectively lack the fast component (I_K,f) of BK_Ca (large-conductance voltage- and Ca²⁺-activated K⁺ channels)

• loss of fast outward K⁺ channels results in marked reduction of overall current amplitudes at all potentials positive to approximately -60 mV

• current-clamp recordings indicate altered presynaptic IHC voltage responses with increased onset and steady-state amplitudes and significantly slower membrane time constants, both for the in vitro resting potential (2x larger) and at a more physiological membrane potential of -58 mV (3x slower) relative to wild-type IHCs

• in vivo, receptor potential-like voltage responses of mutant IHCs show reduced oscillating alternating current (AC) components and increased depolarizing direct current (DC) components while the IHC resting potential appears modestly depolarized relative to wild-type IHCs

• notably, other ionic conductances of mutant IHCs remain normal, as shown by normal expression of Ca²⁺ currents and other K⁺ (delayed outward rectifier and KCNQ-type) currents as well as normal resting membrane potentials (V_R) relative to wild-type IHCs

abnormal hearing electrophysiology ( J:109217 )

abnormal cochlear nerve fiber response ( J:109217 )

• at 7-17 weeks of age, homozygotes show slightly increased mean thresholds (15-20 dB) of individual auditory nerve (AN) fibers at the characteristic frequency (CF, the sensitive ""tip"" of the tuning curve), although a large overlap between wild-type and mant AN fibers is noted in all frequency regions

• surprisingly, both peak and steady-state sound-evoked discharge rates recorded in response to saturating tone bursts are significantly reduced, esp. among high spontaneous rate AN fibers

• in addition, most mutant AN fibers show deteriorated temporal precision of spike timing, i.e. an increased variance of first spike latency by ~2 orders of magnitude in response to tone bursts at CF, consistent with slowed voltage responses in presynaptic IHCs

• a ~2-fold reduction of postsynaptic steady-state AN spike rates is associated with a 20% increase in absolute refractory period of mutant ears

• notably, cochlear sensitivity and sharpness of frequency tuning remain essentially normal, with no significant changes in the range of spontaneous rates, dynamic range of individual AN fibers or shape of tuning curves

increased or absent distortion product otoacoustic emission threshold ( J:109217 )

• at 7-17 weeks of age, homozygotes show slightly elevated DPOAE thresholds at all test frequencies relative to wild-type mice, although significant overlap in DPOAE data is observed

nervous system

abnormal cochlear IHC afferent innervation pattern ( J:109217 )

• mutant IHCs show a reduced number of low (<5 sp/s) spontaneous rate auditory nerve (AN) fibers relative to wild-type (4% vs 18%, respectively), consistent with a slight IHC depolarization in mutant ears

abnormal cochlear inner hair cell physiology ( J:109217 )

• apical IHCs isolated from P22- to P30-old homozygotes selectively lack the fast component (I_K,f) of BK_Ca (large-conductance voltage- and Ca²⁺-activated K⁺ channels)

• loss of fast outward K⁺ channels results in marked reduction of overall current amplitudes at all potentials positive to approximately -60 mV

• current-clamp recordings indicate altered presynaptic IHC voltage responses with increased onset and steady-state amplitudes and significantly slower membrane time constants, both for the in vitro resting potential (2x larger) and at a more physiological membrane potential of -58 mV (3x slower) relative to wild-type IHCs

• in vivo, receptor potential-like voltage responses of mutant IHCs show reduced oscillating alternating current (AC) components and increased depolarizing direct current (DC) components while the IHC resting potential appears modestly depolarized relative to wild-type IHCs

• notably, other ionic conductances of mutant IHCs remain normal, as shown by normal expression of Ca²⁺ currents and other K⁺ (delayed outward rectifier and KCNQ-type) currents as well as normal resting membrane potentials (V_R) relative to wild-type IHCs

abnormal cochlear nerve fiber response ( J:109217 )

• at 7-17 weeks of age, homozygotes show slightly increased mean thresholds (15-20 dB) of individual auditory nerve (AN) fibers at the characteristic frequency (CF, the sensitive ""tip"" of the tuning curve), although a large overlap between wild-type and mant AN fibers is noted in all frequency regions

• surprisingly, both peak and steady-state sound-evoked discharge rates recorded in response to saturating tone bursts are significantly reduced, esp. among high spontaneous rate AN fibers

• in addition, most mutant AN fibers show deteriorated temporal precision of spike timing, i.e. an increased variance of first spike latency by ~2 orders of magnitude in response to tone bursts at CF, consistent with slowed voltage responses in presynaptic IHCs

• a ~2-fold reduction of postsynaptic steady-state AN spike rates is associated with a 20% increase in absolute refractory period of mutant ears

• notably, cochlear sensitivity and sharpness of frequency tuning remain essentially normal, with no significant changes in the range of spontaneous rates, dynamic range of individual AN fibers or shape of tuning curves

Genotype
MGI:3050200

hm2

• Allelic Composition: Kcnma1^tm1Ruth/Kcnma1^tm1Ruth
• Genetic Background: involves: 129/Sv * C57BL/6

behavior/neurological

abnormal eye blink conditioning behavior ( J:91427 )

• no learning of conditioned eye blink is seen

abnormal motor capabilities/coordination/movement ( J:91427 )

increased blinking frequency ( J:91427 )

• increased eye blinking is seen

tremors ( J:91427 )

• intention tremor is seen

ataxia ( J:91427 )

• mutants show obvious ataxia

impaired coordination ( J:91427 )

• mutants are reluctant to cross a balance beam and fall off the beam or start platform, performance in the rotarod and open field tests is also impaired

impaired swimming ( J:91427 )

• swim speed is reduced and more time is spent floating

abnormal gait ( J:91427 )

• irregular step patterns are seen

short stride length ( J:91427 )

cardiovascular system

increased systemic arterial blood pressure ( J:91427 )

• about a 10% increase in arterial blood pressure is seen

growth/size/body

abnormal postnatal growth ( J:91427 )

• by 4 - 8 weeks of age mutants are 15-20% smaller however by 12 weeks no size difference is seen

nervous system

impaired ability to fire action potentials ( J:91427 )

• about 50% of Purkinje cells lack spontaneous discharge and the afterhyperpolarization amplitude is significantly smaller

increased synaptic depression ( J:91427 )

• for intervals shorter than 100 ms paired-pulse depression is enhanced

digestive/alimentary system

abnormal feces composition ( J:135743 )

• reduced K⁺ content

abnormal digestive system physiology ( J:135743 )

• unlike in wild-type mice, luminal UTP does not stimulate K⁺ secretion in the colon

• resting transepithelial voltage in the colon is significantly more lumen negative compared to wild-type controls

• luminal Ba²⁺ or Ca²⁺ ionophore do not alter the transepithelial voltage, unlike in wild-type mice

• amiloride-sensitive Na+ absorption is increased in the distal colon compared to wild-type controls

• however, forskolin-activated NaCl secretion in the colon is similar to wild-type controls

renal/urinary system

abnormal urinary bladder physiology ( J:148424 )

• the iberiotoxin sensitive component of the large noninactivating outward currents induced in urinary bladder smooth muscle cells by membrane depolarization is absent voltage dependent Ca2+ current densities are reduced in urinary bladder smooth muscle cells

• peak contractions are more accentuated and maximal contraction is seen at lower electric field stimulation frequencies in detrusor muscle strips with intact urothelium compared to wild-type controls

• intramural pressures below 10 mmHg are less frequent and pressures above 10 mmHg are more frequent compared to controls

• elevated urinary bladder tone

increased urination frequency ( J:148424 )

• increase in the number of micturitions following intake of a defined amount of fluid

muscle

abnormal muscle contractility ( J:148424 )

• peak contractions are more accentuated and maximal contraction is seen at lower electric field stimulation frequencies in detrusor muscle strips with intact urothelium compared to wild-type controls

• urinary bladder detrusor muscle is more sensitive to isoproterenol and Sp-5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole-3',5'-monophosphorothioate induced inhibition of contractility

increased muscle relaxation ( J:148424 )

• at a stimulation frequency of 30 Hz bladder strips display faster and more pronounced relaxation compared to controls

Genotype
MGI:3629389

hm3

• Allelic Composition: Kcnma1^tm1Ruth/Kcnma1^tm1Ruth
• Genetic Background: involves: 129X1/SvJ

hearing/vestibular/ear

cochlear outer hair cell degeneration ( J:92443 , J:117764 )

• at 14 weeks, homozygotes exhibit severe OHC degeneration in the basal and mid-basal cochlear turns (J:92443)

• at 10 weeks, severe loss of OHCs occurs exclusively in high frequency (HF; midbasal) cochlear turns, whereas low frequency (LF; apical) OHCs remain histologically intact (J:117764)

Deiters cell degeneration ( J:92443 )

• increased apoptosis in Deiters cells at 14 weeks of age

absent distortion product otoacoustic emissions ( J:92443 )

• at >8 weeks, lack of distortion product otoacoustic emissions suggests OHC dysfunction

increased susceptibility to noise-induced hearing loss ( J:117764 )

• at 7 days after exposure to low frequency (LF) band-pass noise (4-8 kHz), 4-5 wk-old homozygotes, but not wild-type mice, exhibit a permanent hearing loss, as validated by click-ABR thresholds

• noise-exposed homozygotes develop a significant hearing loss between 8 and 16 kHz, as validated by frequency-specific ABR thresholds

• in homozygotes, the LF band-pass noise-induced threshold shift is accompanied by a specific loss of KCNQ4 exclusively in medial turns, whereas apical and midbasal/basal turns appear normal

sensorineural hearing loss ( J:92443 )

• at >8 weeks, homozygotes exhibit a slowly progressing high-frequency hearing loss

• no obvious hearing deficits are detected during the first 4 postnatal weeks

• hearing loss is linked to loss of the KCNQ4 potassium channel in OHC membranes in the basal and midbasal cochlear turns, precedes OHC degeneration, and resembles pharmacologic blockade of KCNQ4 channels

nervous system

cochlear outer hair cell degeneration ( J:92443 , J:117764 )

• at 14 weeks, homozygotes exhibit severe OHC degeneration in the basal and mid-basal cochlear turns (J:92443)

• at 10 weeks, severe loss of OHCs occurs exclusively in high frequency (HF; midbasal) cochlear turns, whereas low frequency (LF; apical) OHCs remain histologically intact (J:117764)

cellular

increased apoptosis ( J:92443 )

• in Deiters cells at 14 weeks of age

Genotype
MGI:3845037

cn4

• Allelic Composition: Kcnma1^tm1Ruth/Kcnma1^tm2.1Ruth; X/Tg(Myh11-icre/ERT2)1Soff
• Genetic Background: involves: 129/Sv * C57BL/6 * FVB/N

renal/urinary system

abnormal urinary bladder physiology ( J:148424 )

♂ • the iberiotoxin sensitive component of the large noninactivating outward currents induced in urinary bladder smooth muscle cells by membrane depolarization is absent after tamoxifen treatment

♂ • following tamoxifen treatment, peak contractions are more accentuated and maximal contraction is seen at lower electric field stimulation frequencies in detrusor muscle strips with intact urothelium

♂ • following tamoxifen treatment, peak contractions of detrusor muscle strips with intact urothelium are stronger at stimulation frequencies of 1, 2, and 4 Hz compared to mice homozygous for Kcnma1^tm1Ruth

increased urination frequency ( J:148424 )

♂ • following tamoxifen treatment, an increase in the number of micturitions following intake of a defined amount of fluid is seen compared to both wild-type mice and mice homozygous for Kcnma1^tm1Ruth

muscle

abnormal muscle contractility ( J:148424 )

♂ • following tamoxifen treatment, peak contractions are more accentuated and maximal contraction is seen at lower electric field stimulation frequencies in detrusor muscle strips with intact urothelium compared to wild-type controls

♂ • following tamoxifen treatment, urinary bladder detrusor muscle is more sensitive to isoproterenol and Sp-5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole-3',5'-monophosphorothioate induced inhibition of contractility compared to controls

♂ • following tamoxifen treatment, peak contractions of detrusor muscle strips with intact urothelium are stronger at stimulation frequencies of 1, 2, and 4 Hz compared to mice homozygous for Kcnma1^tm1Ruth