Phenotypes associated with this allele

• Allele Symbol: Slc6a9^tm1Betz
• Allele Name: targeted mutation 1, Heinrich Betz
• Allele ID: MGI:2682493
• Summary: 1 genotype

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Slc6a9^tm1Betz/Slc6a9^tm1Betz	involves: 129P2/OlaHsd * C57BL/6	MGI:2682534

Genotype
MGI:2682534

hm1

• Allelic Composition: Slc6a9^tm1Betz/Slc6a9^tm1Betz
• Genetic Background: involves: 129P2/OlaHsd * C57BL/6

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

mortality/aging

neonatal lethality, complete penetrance ( J:86624 )

• newborn homozygotes are externally normal but gradually fail to thrive and die within 6-14 hrs after birth most likely due to respiratory failure combined with an inability to suckle

behavior/neurological

lethargy ( J:86624 )

absent gastric milk in neonates ( J:86624 )

• newborn homozygotes lack milk in their stomachs

abnormal suckling behavior ( J:86624 )

• newborn homozygotes are unable to suckle

hyporesponsive to tactile stimuli ( J:86624 )

• newborn homozygotes are hyporesponsive to mild tactile stimuli such as gentle touch

• when picked up and nipped by their tail, newborn homozygotes display only a weak (8/10) or no (2/10) tail pinching response

abnormal limb posture ( J:86624 )

• upon mild tactile stimulation, newborn homozygotes assume an abnormal body posture with dropping forelimbs

bradykinesia ( J:86624 )

• newborn homozygotes display only weak or no spontaneous motor activity

respiratory system

abnormal breathing pattern ( J:86624 )

• newborn homozygotes display a severe breathing irregularity

• however, no histologic abnormalities of the airways or lungs are observed and the musculo-skeletal system appears unaffected

decreased pulmonary respiratory rate ( J:86624 )

• newborn homozygotes show a severe depression of respiratory frequencies to only 16% of those in wild-type pups, as shown by whole-body plethysmography

• although durations of single breaths are only marginally longer, expiratory intervals are significantly prolonged as shown by a 4-fold increase of the coefficient of variation relative to that in control littermates

apnea ( J:86624 )

• newborn homozygotes exhibit long periods of apnea interrupted by gasp-like inspirations

respiratory distress ( J:86624 )

• newborn homozygotes exhibit long periods of apnea interrupted by gasp-like inspirations

growth/size/body

decreased body weight ( J:86624 )

• newborn homozygotes weigh ~15% less than control littermates

homeostasis/metabolism

dehydration ( J:86624 )

muscle

hypotonia ( J:86624 )

nervous system

nervous system phenotype ( J:86624 )

N • newborn homozygotes display normal brain stem and spinal cord histology

N • no major adaptive changes in synapse biochemistry or differences in synaptic protein expression are observed in the CNS

N • the density and morphology of glial cells appear unaffected

abnormal nervous system physiology ( J:86624 )

• P2 membrane fractions from newborn homozygotes show a >70% and >80% reduction of [³H]glycine uptake in frontal brain and CNS caudal regions, respectively, relative to wild-type controls

• increased accumulation of extracellular glycine leads to a sustained activation of inhibitory glycine receptors and results in suppression of the respiratory network activity

abnormal nervous system electrophysiology ( J:86624 )

• in vitro analysis of inspiratory activity in mutant brain stem slices indicates prolonged periods of inactivity and a significantly reduced burst frequency with variable interburst intervals relative to the regular rhythmic bursting observed in control slices

• application of the glycine receptor antagonist strychnine (2 uM) increases burst activity by 3.6-fold leading to a frequency comparable to that seen under control conditions in wild-type mice; however, the activity of mutant slices is consistently more irregular than that of wild-type preparations

• the coefficient of variation of the interburst interval is significantly higher in mutant slices and is only partially improved upon strychnine application

• however, no differences in rise time and burst duration are observed between brain stem slices from wild-type and mutant mice

• application of the GABA_A receptor antagonist bicuculline (1-2 uM) fails to normalize the rhythmic burst patterns observed in mutant slices

• application of the NMDA receptor blockers MK-801 (10 uM) and AP-5 (100 uM) fails to restore a regular respiratory rhythm in mutant slices

abnormal inhibitory postsynaptic currents ( J:86624 )

• whole-cell recordings from hypoglossal motoneurons at a holding potential of -70 mV indicate that during periods without obvious IPSCs, the average noise values recorded from mutant neurons are significantly higher than those observed in wild-type cells

• the average interval of IPSCs identified in mutant hypoglossal motoneurons is significantly lower than in wild-type cells, whereas the average IPSC amplitude is not significantly smaller than that in wild-type cells

• the IPSC decay time is significantly longer in mutant neurons relative to wild-type cells

• application of strychnine decreases the steady-state holding current in mutant hypoglossal motoneurons and reduces synaptic noise to wild-type levels

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
glycine encephalopathy		DOID:9268	OMIM:PS605899	J:86624