Phenotypes associated with this allele

• Allele Symbol: S1pr2^tm1Ajml
• Allele Name: targeted mutation 1, A John MacLennan
• Allele ID: MGI:2180817
• Summary: 3 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	S1pr2^tm1Ajml/S1pr2^tm1Ajml	129S5/SvEvBrd-S1pr2^tm1Ajml	MGI:5882507
hm2	S1pr2^tm1Ajml/S1pr2^tm1Ajml	either: (involves: 129S5/SvEvBrd) or (involves: 129S5/SvEvBrd * C57BL/6)	MGI:3692665
hm3	S1pr2^tm1Ajml/S1pr2^tm1Ajml	involves: 129S5/SvEvBrd * C57BL/6	MGI:3663255

Genotype
MGI:5882507

hm1

• Allelic Composition: S1pr2^tm1Ajml/S1pr2^tm1Ajml
• Genetic Background: 129S5/SvEvBrd-S1pr2^tm1Ajml

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

neoplasm

increased B cell derived lymphoma incidence ( J:154439 )

• 66% of mice develop clonal B-cell lymphoma by 18-24 months of age

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
non-Hodgkin lymphoma		DOID:0060060	OMIM:605027	J:154439

Genotype
MGI:3692665

hm2

• Allelic Composition: S1pr2^tm1Ajml/S1pr2^tm1Ajml
• Genetic Background: either: (involves: 129S5/SvEvBrd) or (involves: 129S5/SvEvBrd * C57BL/6)

mortality/aging

premature death ( J:112371 )

• Background Sensitivity: on a 50:50 129SvEvBrd:C57BL/6 background homozygotes exhibit a ~15% overall death rate from seizures; however, on a pure 129SvEvBrd background the overall death rate drops below 5%

behavior/neurological

impaired swimming ( J:112371 )

• 42.9% of aging homozygotes (aged 70 days or older) exhibit impaired swimming ability, in the absence of overt motor dysfunction

head tilt ( J:112371 )

• 45.7% of aging homozygotes (aged 70 days or older) exhibit tilted heads

seizures ( J:112371 )

• Background Sensitivity: on a 50:50 129SvEvBrd:C57BL/6 background, some homozygotes display rare (mean <4 during lifespan), brief (mean <5 s) seizures; on a pure 129SvEvBrd background, the period of seizure susceptibility is reduced by ~75%; no seizures and death are noted on a purified C57BL/6NCrlBr background

hearing/vestibular/ear

otosclerosis ( J:112371 )

• occasional otosclerosis is detected well after the onset of hearing loss

detached Reissner membrane ( J:112371 )

• in some cases, Reissner's membrane exits distant from its typical emergence from the upper limit of the stria vascularis

• in other cases, it appears to be partially collapsed over the stria vascularis

abnormal Rosenthal canal morphology ( J:112371 )

• Rosenthal's canal is progressively and completely depleted of cell bodies and processes with increasing age

cochlear outer hair cell degeneration ( J:112371 , J:231927 )

• cochlear OHCs are lost with increasing age to a greater extent than in control inner ears (J:112371)

organ of Corti degeneration ( J:112371 )

• by 3 weeks, the tunnel of Corti/Nuel's space structures are consistently abnormal

• with time, many structures of the organ of Corti are completely lost

thin stria vascularis ( J:112371 , J:231927 )

• aging homozygotes exhibit a much thinner stria vascularis (J:112371)

abnormal tectorial membrane morphology ( J:112371 )

• in older homozygotes, the tectorial membrane is encased in a membrane-like cover, shows fiber-like striations, and is tilted from the site where the organ of Corti would lie

• commonly, epithelial-like cells form "nests" at the site where Reissner's membrane and the tectorial membrane lie together in both basal and apical cochlear turns

• basal cochlear turns are more affected, consistent with the only ABR signal from mutant mice being in response to the lowest frequency tone

small scala media ( J:112371 )

• the scala media portion of the cochlear labyrinth is reduced with increasing age

vestibular saccular degeneration ( J:112371 )

• at one year, homozygotes display significant saccular degeneration

decreased otolith number ( J:112371 , J:231927 )

• aging homozygotes display decreases in the otoconia of both the utricle and saccule relative to age-matched controls (J:112371)

• loss of utricular otoconia precedes the vestibular defects (head tilt and swimming) and does not predict the behavioral defects as well as the loss of saccular otoconia (J:112371)

increased or absent threshold for auditory brainstem response ( J:112371 )

• homozygotes show no ABR responses at 100 dB (highest intensity tested); the threshold, were there to be any response, would thus be >100 dB

deafness ( J:112371 , J:231927 )

• as early as P22, 100% of homozygotes are profoundly deaf, as shown by lack of auditory evoked brainstem (ABR) responses, while the vestibular defects are present in 40-50% of mutant mice (J:112371)

• at P22, one homozygote showed a slight response to very high intensity (90 dB) 8 kHz tones but failed to respond to 100 dB clicks, 16 kHz tones or 32 kHz tones; all other homozygotes failed to respond to all tones and clicks (J:112371)

• both old and young homozygotes fail to display any of the expected ABR peaks, suggesting defects in peripheral components of the auditory system (J:112371)

abnormal vestibular system physiology ( J:112371 )

• aging homozygotes show signs of vestibular dysfunction e.g. head tilt and impaired swimming

nervous system

seizures ( J:112371 )

• Background Sensitivity: on a 50:50 129SvEvBrd:C57BL/6 background, some homozygotes display rare (mean <4 during lifespan), brief (mean <5 s) seizures; on a pure 129SvEvBrd background, the period of seizure susceptibility is reduced by ~75%; no seizures and death are noted on a purified C57BL/6NCrlBr background

cochlear outer hair cell degeneration ( J:112371 , J:231927 )

• cochlear OHCs are lost with increasing age to a greater extent than in control inner ears (J:112371)

skeleton

otosclerosis ( J:112371 )

• occasional otosclerosis is detected well after the onset of hearing loss

craniofacial

otosclerosis ( J:112371 )

• occasional otosclerosis is detected well after the onset of hearing loss

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
autosomal recessive nonsyndromic deafness 68		DOID:0110519	OMIM:610419	J:231927

Genotype
MGI:3663255

hm3

• Allelic Composition: S1pr2^tm1Ajml/S1pr2^tm1Ajml
• Genetic Background: involves: 129S5/SvEvBrd * C57BL/6

nervous system

seizures ( J:73957 )

• unexpectedly, homozygotes display normal brain cytoarchitecture, peripheral axon growth and neurological development, with no postnatal motor/sensory dysfunction or defects in hippocampal and neocortical development

• however, between 3 and 7 wks of age, homozygotes display spontaneous, intermittent sporadic seizures of variable timing occurring in clusters of 3 or more per hr during 1-4-day periods within the susceptible interval

• ~85% of seizures are characterized by 2-10-sec wild running episodes followed by 15-60-sec periods of freezing

• the vast majority of severely affected homozygotes survive the susceptible period and recover

tonic-clonic seizures ( J:73957 )

• ~15% of seizures are characterized by 2-10 sec wild running episodes followed by tonic-clonic convulsions; 2% of these are lethal

abnormal nervous system electrophysiology ( J:73957 )

abnormal action potential ( J:73957 )

• under current clamp, 10 of 14 mutant neocortical pyramidal neurons exhibit spontaneous paroxysmal depolarizing shifts and bursts of action potentials

• addition of GABA_A receptor antagonist bicuculline methiodide increases burst frequency and results in a prolonged depolarization with repetitive action potentials in 4 of the cells

• in the presence of bicuculline, electrically evoked epileptiform depolarization responses are augmented in mutant cells relative to wild-type cells

abnormal brain wave pattern ( J:73957 )

• spontaneous seizures are accompanied by ictal-like EEG abnormalities and hyperexcitable neocortical pyramidal neurons

abnormal CNS synaptic transmission ( J:73957 )

abnormal excitatory postsynaptic currents ( J:73957 )

• homozygotes show significant increases in both the frequency and amplitude of spontaneous EPSCs

• the ampliture of electrically evoked EPSCs is also markedly increased in the absence of pharmacological or ionic enhancement

increased excitatory postsynaptic current amplitude ( J:73957 )

• of spontaneous EPSCs

increased excitatory postsynaptic current frequency ( J:73957 )

• of spontaneous EPSCs

behavior/neurological

seizures ( J:73957 )

• unexpectedly, homozygotes display normal brain cytoarchitecture, peripheral axon growth and neurological development, with no postnatal motor/sensory dysfunction or defects in hippocampal and neocortical development

• however, between 3 and 7 wks of age, homozygotes display spontaneous, intermittent sporadic seizures of variable timing occurring in clusters of 3 or more per hr during 1-4-day periods within the susceptible interval

• ~85% of seizures are characterized by 2-10-sec wild running episodes followed by 15-60-sec periods of freezing

• the vast majority of severely affected homozygotes survive the susceptible period and recover

tonic-clonic seizures ( J:73957 )

• ~15% of seizures are characterized by 2-10 sec wild running episodes followed by tonic-clonic convulsions; 2% of these are lethal

hematopoietic system

increased germinal center B cell number ( J:154439 )

• increase in germinal center B cells in 9-12 month old mice before tumor formation

increased T cell number ( J:154439 )

• increase in germinal center CD69+ T cells in 9-12 month old mice before tumor formation

increased spleen germinal center number ( J:154439 )

• spleens show an increase in number of spontaneous germinal centers at 9-12 months of age before tumor formation

increased spleen germinal center size ( J:154439 )

• spleens show an increase in size of spontaneous germinal centers at 9-12 months of age before tumor formation

abnormal spleen marginal zone morphology ( J:154439 )

• benign splenic marginal zone hyperplasia

immune system

increased germinal center B cell number ( J:154439 )

• increase in germinal center B cells in 9-12 month old mice before tumor formation

increased T cell number ( J:154439 )

• increase in germinal center CD69+ T cells in 9-12 month old mice before tumor formation

increased spleen germinal center number ( J:154439 )

• spleens show an increase in number of spontaneous germinal centers at 9-12 months of age before tumor formation

increased spleen germinal center size ( J:154439 )

• spleens show an increase in size of spontaneous germinal centers at 9-12 months of age before tumor formation

abnormal spleen marginal zone morphology ( J:154439 )

• benign splenic marginal zone hyperplasia

neoplasm

increased B cell derived lymphoma incidence ( J:154439 )

• mice develop clonal B-cell lymphomas with age, such that 50% of mice show neoplasm by 1.5-2 years of age

• tumors show features of germinal center-derived diffuse large B-cell lymphoma

• tumors are seen in mesenteric, submandibular, and mediastinal lymph nodes, in the spleen, and rarely in the liver and retroperitoneal soft tissue, with frequent involvement of multiple sites within individual mice

increased lung tumor incidence ( J:154439 )

• a very low incidence of lung tumors is seen and these are adenocarcinomas or very large lung adenoma classified as carcinoma due to size

respiratory system

increased lung tumor incidence ( J:154439 )

• a very low incidence of lung tumors is seen and these are adenocarcinomas or very large lung adenoma classified as carcinoma due to size

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
non-Hodgkin lymphoma		DOID:0060060	OMIM:605027	J:154439