Phenotypes associated with this allele

• Allele Symbol: Nhlh1^tm1Irk
• Allele Name: targeted mutation 1, Ilan R Kirsch
• Allele ID: MGI:2183573
• Summary: 3 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Nhlh1^tm1Irk/Nhlh1^tm1Irk	involves: 129S4/SvJae	MGI:3626205
cx2	Nhlh1^tm1Irk/Nhlh1^tm1Irk Nhlh2^tm1Irk/Nhlh2^tm1Irk	involves: 129S4/SvJae * C57BL/6	MGI:3626206
cx3	Nhlh1^tm1Irk/Nhlh1^tm1Irk Nhlh2^tm1Irk/Nhlh2^+	involves: 129S4/SvJae * C57BL/6	MGI:3626207

Genotype
MGI:3626205

hm1

• Allelic Composition: Nhlh1^tm1Irk/Nhlh1^tm1Irk
• Genetic Background: involves: 129S4/SvJae

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

mortality/aging

premature death ( J:78031 )

• adult homozygotes are viable, fertile and overtly healthy with no evidence of epilepsy, myocardial infarction or CNS, skeletal or cardiac morphological abnormalities; however, ~25% of homozygotes die by 1 year of age, probably due to a predisposition to ventricular arrhythmias

cardiovascular system

decreased heart rate variability ( J:78031 )

• at 10 and 12 months of age, homozygotes display a significant reduction in total heart rate power (an index of heart rate variability) relative to wild-type mice (14.2 1.96 ms² vs 31.7 6.11 ms², respectively)

• in addition, homozygotes exhibit a slight increase in the low-frequency-to-high-frequency heart rate variability ratio relative to wild-type mice (2.23 0.653 vs 1.16 0.166, respectively), suggesting reduced parasympathetic activation

irregular heartbeat ( J:78031 )

• in response to sudden water immersion, homozygotes fail to exhibit a transient diving-induced bradycardia, indicating absence of a vagal response; an increased heart rate (644 40 bpm vs 569 34 bpm in wild-type) is observed for the first 30 beats after immersion

ventricular premature beat ( J:78031 )

• in response to swimming stress, ECGs from homozygotes exhibit premature ventricular complexes, couplets, and triplets during swimming while wild-type ECGs show only isolated ventricular escape beats during ""diving""-induced atrioventricular block

abnormal QT variability ( J:78031 )

• at 10 and 12 months of age, homozygotes show no differences in mean QT interval or heart rate-corrected QT interval [QT_c] relative to wild-type mice, indicating absence of a long QT syndrome

• however, homozygotes display a significantly higher, positive number in the QT variability index (normally a unitless negative number) than wild-type mice (0.17 0.142 vs -0.39 0.176, respectively), indicating increased repolarization lability

nervous system

abnormal parasympathetic nervous system physiology ( J:78031 )

• homozygotes exhibit a decreased total heart rate variability, a reduced diving reflex, and impaired baroreceptor sensitivity, indicating a functional parasympathetic deficit in the absence of heart structural abnormalities

• in contrast, sympathetic activity appears unaffected, as measured by total beta-adrenergic receptor density in myocardial membranes

Genotype
MGI:3626206

cx2

• Allelic Composition: Nhlh1^tm1Irk/Nhlh1^tm1Irk; Nhlh2^tm1Irk/Nhlh2^tm1Irk
• Genetic Background: involves: 129S4/SvJae * C57BL/6

mortality/aging

mortality/aging ( J:78031 )

N • double homozygotes die perinatally in apparent cardiorespiratory distress

Genotype
MGI:3626207

cx3

• Allelic Composition: Nhlh1^tm1Irk/Nhlh1^tm1Irk; Nhlh2^tm1Irk/Nhlh2⁺
• Genetic Background: involves: 129S4/SvJae * C57BL/6

mortality/aging

premature death ( J:78031 )

• ~45% of mice homozygous for Nhlh1^tm1Irk and heterozygous for Nhlh2^tm1Irk die by 1 year of age, probably due to an increased predisposition to ventricular arrhythmias

cardiovascular system

decreased heart rate variability ( J:78031 )

• mice homozygous for Nhlh1^tm1Irk and heterozygous for Nhlh2^tm1Irk display a significant reduction in total heart rate power (an index of heart rate variability) relative to wild-type mice (17.2 3.26 ms² vs 31.7 6.11 ms², respectively)

• in addition, these mutants exhibit a significant increase in the low-frequency-to-high-frequency heart rate variability ratio relative to wild-type mice (3.77 0.833 vs 1.16 0.166, respectively), suggesting reduced parasympathetic activation

irregular heartbeat ( J:78031 )

• in response to sudden water immersion, mutants fail to exhibit a transient diving-induced bradycardia, suggesting absence of a vagal response; a further increase in heart rate relative to Nhlh1^tm1Irk homozygotes (717 19 bpm vs 644 40 bpm, respectively) is observed for the first 30 beats after immersion

ventricular fibrillation ( J:78031 )

• in response to swimming stress, 1 of 8 mutants developed a rapid rhythm (800-850 bpm) following immersion without consistent atrial activity; the mouse abruptly ceased swimming and, after a burst of chaotic electrical activity, developed an agonal bradycardia despite removal from the water, consistent with ventricular fibrillation

ventricular premature beat ( J:78031 )

• in response to swimming stress, ECGs from these mutants exhibit premature ventricular complexes, couplets, and triplets during swimming while wild-type ECGs show only isolated ventricular escape beats during ""diving""-induced atrioventricular block

abnormal QT variability ( J:78031 )

• mice homozygous for Nhlh1^tm1Irk and heterozygous for Nhlh2^tm1Irk display a further increase in the QTVI index relative to Nhlh1^tm1Irk homozygotes (0.42 0.148 vs 0.17 0.142, respectively), indicating a severely augmented repolarization lability

nervous system

abnormal parasympathetic nervous system physiology ( J:78031 )

• mutant mice exhibit an augmented reduction in total heart rate variability, diving reflex, and baroreceptor sensitivity relative to Nhlh1^tm1Irk homozygotes, indicating a more severe functional parasympathetic deficit

• in contrast, sympathetic activity appears unaffected, as measured by total beta-adrenergic receptor density in myocardial membranes

behavior/neurological

abnormal reflex ( J:78031 )

• despite a normal resting systolic blood pressure and pulse, mutant mice exhibit loss of the diving reflex as well as a significant reduction in baroreceptor sensitivity to pharmacologically-induced changes in mean blood pressure, indicating reduced reflex vagal activity