Phenotypes associated with this allele

• Allele Symbol: Hcn1^tm2Kndl
• Allele Name: targeted mutation 2, Eric R Kandel
• Allele ID: MGI:2686951
• Summary: 4 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Hcn1^tm2Kndl/Hcn1^tm2Kndl	involves: 129 * 129S/SvEv * C57BL/6J * C57BL/6N	MGI:5688197
hm2	Hcn1^tm2Kndl/Hcn1^tm2Kndl	involves: 129S/SvEv * C57BL/6	MGI:2686970
hm3	Hcn1^tm2Kndl/Hcn1^tm2Kndl	involves: 129S/SvEv * C57BL/6J	MGI:5140000
cx4	Hcn1^tm2Kndl/Hcn1^tm2Kndl Or8a1b^tm6Mom/Or8a1b^tm6Mom	involves: 129P2/OlaHsd * 129S/SvEv * C57BL/6J	MGI:4849470

Genotype
MGI:5688197

hm1

• Allelic Composition: Hcn1^tm2Kndl/Hcn1^tm2Kndl
• Genetic Background: involves: 129 * 129S/SvEv * C57BL/6J * C57BL/6N

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

cardiovascular system

decreased cardiac output ( J:219164 )

• reduction in cardiac output to 69% of wild-type

• however, stroke volume is normal

abnormal heartbeat ( J:219164 )

• mice exhibit congenital sinus node dysfunction characterized by bradycardia, sinus dysrhythmia, prolonged sinoatrial node recovery time, increased sinoatrial conduction time, and recurrent sinus pauses

• however, echocardiographic analysis indicates normal cardiac structure, diastolic function, and systolic function and cardiac morphology

increased heart rate variability ( J:219164 )

• mutants exhibit an increase in heart rate variability

• intact sinoatrial node preparations exhibit pronounced fluctuations of the beat-to-beat interval

sinus bradycardia ( J:219164 )

• in vivo telemetric long-term ECG in freely moving mutants and echocardiographic analysis indicates a sinus bradycardia characterized by lower mean heart rates by 16% compared to wild-type and more frequent episodes of low heart rate

• bradycardia is not due to an increase in resting phases because mutants exhibit the same activity and resting behavior as wild-type mice

• beta-adrenergic stimulation with isoproterenol results in the same relative increase in heart rate as in wild-type mice, however the maximum heart rate is lower in mutants

• intact sinoatrial node preparations show a reduced firing rate of spontaneous pacemaker potentials by 29% compared with wild-type

• isolated perfused hearts exhibit a reduction in beating rate by 20.2%

• isolated sinoatrial pacemaker cells show a shifted resting membrane potential to more hyperpolarized potentials, and a reduced firing rate (by 13%), indicating reduced beating frequency

abnormal RR interval ( J:219164 )

• dramatic fluctuations of the RR interval; fluctuations in RR interval are more pronounced during phases of slow heart rate

abnormal sinoatrial node conduction ( J:219164 )

• intracardiac electrophysiological analysis indicates increased sinus node recovery time, indicating a delayed impulse formation within the sinoatrial node

• atrial pacing (continuously for 10 seconds at 10 Hz) of isolated right atrial preparation containing the sinoatrial node indicates an increase in sinus node recovery time

• isolated central pacemaker cells, both spindle cells and elongated cells, show reduced amplitude of I(f) current in response to hyperpolarizing voltage steps and slowing of the activation kinetics of I(f) current

• however, atrioventricular conduction is normal

sinoatrial block ( J:219164 )

• premature atrial stimulation indicates a prolonged sinoatrial conduction time independent of changes in sinus cycle lengths, indicating impaired impulse propagation and sinoatrial exit block

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
sick sinus syndrome		DOID:13884	OMIM:163800 OMIM:608567	J:219164

Genotype
MGI:2686970

hm2

• Allelic Composition: Hcn1^tm2Kndl/Hcn1^tm2Kndl
• Genetic Background: involves: 129S/SvEv * C57BL/6

behavior/neurological

behavior/neurological phenotype ( J:86763 )

N • basic motor functions were all normal

abnormal learning/memory/conditioning ( J:86763 )

abnormal eye blink conditioning behavior ( J:86763 )

• a deficiency was observed in latency to peak conditioned response

abnormal motor learning ( J:86763 )

• there is a learned motor skill deficit in a rotorod test

• impairment apparently involves learning and memory of relatively fast coordinated movements

abnormal spatial learning ( J:86763 )

• impaired learning in a water maze test

increased thigmotaxis ( J:86763 )

• observed during water maze tests

cardiovascular system

abnormal myocardial fiber physiology ( J:188823 )

• during late polarization, epicardial ventricular myocyte action potentials are shorter than in wild-type cells

• however, early repolarization is normal

nervous system

abnormal action potential ( J:188823 )

• during late polarization, epicardial ventricular myocyte action potentials are shorter than in wild-type cells

• however, early repolarization is normal

Genotype
MGI:5140000

hm3

• Allelic Composition: Hcn1^tm2Kndl/Hcn1^tm2Kndl
• Genetic Background: involves: 129S/SvEv * C57BL/6J

behavior/neurological

abnormal depression-related behavior ( J:173355 )

• mice exhibit less time immobile in forced swim and tail suspension tests compared with wild-type mice

Genotype
MGI:4849470

cx4

• Allelic Composition: Hcn1^tm2Kndl/Hcn1^tm2Kndl; Or8a1b^tm6Mom/Or8a1b^tm6Mom
• Genetic Background: involves: 129P2/OlaHsd * 129S/SvEv * C57BL/6J

nervous system

abnormal olfactory sensory neuron morphology ( J:166733 )

• shortened neurite length in primary cultures of olfactory sensory neurons

abnormal olfactory bulb morphology ( J:166733 )

• although OLFR160 glomeruli have a normal position, the dorsomedial OLFR1507 glomeruli are abnormally positioned caudal rather than rostral to the first accessory olfactory bulb

abnormal olfactory bulb development ( J:166733 )

• at embryonic day 17 protoglomeruli formation is delayed, at 4 days of age glomeruli can be identified but are poorly formed and lack discrete boundaries, and in the adult the glomeruli remain irregularly shaped and not well circumscribed

abnormal olfactory bulb layer morphology ( J:166733 )

• the division of the inner and outer nerve layers of the olfactory bulb is perturbed

abnormal olfactory bulb glomerular layer morphology ( J:166733 )

• although the number of glomeruli and their regional distribution are normal, the glomeruli from the dorsal olfactory bulb are larger than normal and more glomeruli are radially stacked resutling in abnormal lamination

abnormal olfactory bulb outer nerve layer morphology ( J:166733 )

craniofacial

abnormal olfactory sensory neuron morphology ( J:166733 )

• shortened neurite length in primary cultures of olfactory sensory neurons

respiratory system

abnormal olfactory sensory neuron morphology ( J:166733 )

• shortened neurite length in primary cultures of olfactory sensory neurons

taste/olfaction

abnormal olfactory sensory neuron morphology ( J:166733 )

• shortened neurite length in primary cultures of olfactory sensory neurons

growth/size/body

abnormal olfactory sensory neuron morphology ( J:166733 )

• shortened neurite length in primary cultures of olfactory sensory neurons