Phenotypes associated with this allele

• Allele Symbol: Slc9a6^tm1Dgen
• Allele Name: targeted mutation 1, Deltagen
• Allele ID: MGI:3604561
• Summary: 4 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Slc9a6^tm1Dgen/Slc9a6^tm1Dgen	B6.129P2-Slc9a6^tm1Dgen/J	MGI:5902072
ht2	Slc9a6^tm1Dgen/Slc9a6^+	B6.129P2-Slc9a6^tm1Dgen/J	MGI:5902076
ot3	Slc9a6^tm1Dgen/Y	B6.129P2-Slc9a6^tm1Dgen/J	MGI:5902071
ot4	Slc9a6^tm1Dgen/Y	involves: 129P2/OlaHsd * C57BL/6	MGI:3628583

Genotype
MGI:5902072

hm1

• Allelic Composition: Slc9a6^tm1Dgen/Slc9a6^tm1Dgen
• Genetic Background: B6.129P2-Slc9a6^tm1Dgen/J

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

mortality/aging

postnatal lethality, incomplete penetrance ( J:241124 )

♀ • premature death of around 3 weeks of age is seen in some mice

behavior/neurological

behavior/neurological phenotype ( J:241124 )

♀N • unprovoked clinical seizures are not seen

homeostasis/metabolism

abnormal brain cholesterol level ( J:241124 )

♀ • unesterified cholesterol is detected in cells of the basolateral amygdala which is not seen in wild-type neurons

increased ganglioside level ( J:241124 )

♀ • GM2 ganglioside accumulation, particularly in the basolateral nuclei of the amygdala, occurs specifically in late endosomes and lysosomes

♀ • GM2 ganglioside accumulation in neurons is more prominent in homozygous females than in hemizygous males

♀ • by 12 weeks of age, GM2 accumulation is also seen in neurons of CA3 and CA4 regions and the inner dentate gyrus of the hippocampus, as well as hypothalamus, fasciola cinereum, and piriform cortex

♀ • however, accumulation of GM1, GM3 or GD3 gangliosides in the brain is not seen

abnormal enzyme/coenzyme activity ( J:241124 )

♀ • no active beta-hexosaminidase enzyme activity, the lysosomal enzyme responsible for GM2 degradation, is seen in neurons storing GM2 ganglioside

nervous system

abnormal brain morphology ( J:241124 )

♀ • small increase in hyperphosphorylated tau are seen in soluble brain fractions

abnormal brain cholesterol level ( J:241124 )

♀ • unesterified cholesterol is detected in cells of the basolateral amygdala which is not seen in wild-type neurons

abnormal amygdala morphology ( J:241124 )

♀ • GM2 ganglioside accumulation in late endosomes and lysosomes in the basolateral nuclei of the amygdala

♀ • cholesterol sequestration in neurons of the amygdala

♀ • some amygdala neurons exhibit singular, non-membrane-bound structures resembling aggresomes or one or more membrane-bound lysosomal-like inclusions composed of dense matrix in the cytoplasm

♀ • some neurons in the amygdala exhibit an abnormal distribution of vesicular organalles corralled near the Golgi and trans-Golgi network with other perikaryal regions appearing organelle deficient

♀ • nuclei of neurons in the amygdala are often lobulated excessively and/or multiple number of nucleoi are seen

abnormal cerebral cortex morphology ( J:241124 )

♀ • some neurons in the cerebral cortex exhibit an abnormal distribution of vesicular organelles corralled near the Golgi and trans-Golgi network with other perikaryal regions appearing organelle deficient

♀ • however, cerebral cortex and subcortical regions do not show evidence of lysosomal storage

abnormal neuron morphology ( J:241124 )

♀ • increase in the number of lysosomes in neurons storing GM2 ganglioside

♀ • cholesterol and GM2 ganglioside sequestration occurs in the same neurons of the amygdala, but the two substrates are segregated to different subcellular vesicular populations

♀ • the cytoplasm of some amygdala neurons exhibits singular, non-membrane-bound structures resembling aggresomes or one or more membrane-bound lysosomal-like inclusions composed of a dense matrix

♀ • some neurons in the amygdala and cerebral cortex exhibit an abnormal distribution of vesicular organelles corralled near the Golgi and trans-Golgi network with other perikaryal regions appearing organelle deficient

♀ • neurons with GM2 ganglioside storage contain multiple, large loose-lamellar vesicles resembling storage bodies

♀ • nuclei of neurons in the amygdala and elsewhere are often lobulated excessively and/or multiple number of nucleoi are seen

Purkinje cell degeneration ( J:241124 )

♀ • extensive and progressive loss of Purkinje cells in the cerebellum

♀ • loss of Purkinje cells occurs in a regular pattern of parasagittal stripes in the cerebellar vermis and hemispheres

abnormal Purkinje cell axon morphology ( J:241124 )

♀ • presence of Purkinje cell axonal spheroids

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
Christianson syndrome		DOID:0060825	OMIM:300243	J:241124

Genotype
MGI:5902076

ht2

• Allelic Composition: Slc9a6^tm1Dgen/Slc9a6⁺
• Genetic Background: B6.129P2-Slc9a6^tm1Dgen/J

behavior/neurological

abnormal spatial reference memory ( J:229166 )

♀ • females exhibit deficits in visuospatial memory in the hippocampus-dependent object placement test at 20-22 weeks of age, failing to display a preference for a relocated object

impaired coordination ( J:229166 )

♀ • females exhibit motor coordination defects on the balance beam

♀ • however, no females exhibit obvious ataxia at 32-34 weeks of age and females do not differ in track length, rears, or anxiety-like behavior

homeostasis/metabolism

increased ganglioside level ( J:229166 )

♀ • GM2 ganglioside accumulation in neurons of hippocampal CA3/CA4 regions and the amygdala

nervous system

abnormal amygdala morphology ( J:229166 )

♀ • GM2 ganglioside accumulation in neurons of the amygdala

abnormal hippocampus CA3 region morphology ( J:229166 )

♀ • GM2 ganglioside accumulation in neurons of hippocampal CA3/CA4 regions

abnormal hippocampus CA4 region morphology ( J:229166 )

♀ • GM2 ganglioside accumulation in neurons of hippocampal CA3/CA4 regions

Purkinje cell degeneration ( J:229166 )

♀ • progressive cerebellar Purkinje cell degeneration that is already seen in 4 week old mice

♀ • 32 week old females show a lower extent of Purkinje cell degeneration than males

decreased Purkinje cell number ( J:262453 )

♀ • 5 month old mice exhibit decreased Purkinje cell density

gliosis ( J:229166 )

♀ • females exhibit secondary gliosis in the molecular layer of lobules affected by Purkinje cell degeneration but to a lower degree than in males

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
Christianson syndrome		DOID:0060825	OMIM:300243	J:229166

Genotype
MGI:5902071

ot3

• Allelic Composition: Slc9a6^tm1Dgen/Y
• Genetic Background: B6.129P2-Slc9a6^tm1Dgen/J

behavior/neurological

behavior/neurological phenotype ( J:241124 )

♂N • mice perform similarly to wild-type mice in the object placement test of spatial memory with a 20 minute retention interval - age not specified

♂N • unprovoked clinical seizures are not seen

abnormal spatial reference memory ( J:229166 )

♂ • males exhibit deficits in visuospatial memory in the hippocampus-dependent object placement test at 20-22 weeks of age, failing to display a preference for a relocated object

ataxia ( J:229166 )

♂ • gross ataxia and motor incoordination are not seen at 20-22 weeks of age but are readily seen at 32-34 weeks of age

impaired coordination ( J:229166 , J:241124 )

♂ (J:229166)

♂ • mice exhibit a higher number of slips and longer latency to cross the beam in the balance beam test, indicating motor coordination defects (J:241124)

♂ • however, gross ataxia is not seen (J:241124)

increased vertical activity ( J:241124 )

♂ • increase in the number of rears

increased locomotor activity ( J:229166 , J:241124 )

♂ • 32-34 week old males exhibit increased locomotor activity in the open field and increased exploration (J:229166)

♂ • mice show a longer total track length and an increase in the number of rears in the open field, indicating a modest motor hyperactivity (J:241124)

♂ • however, no indication of anxiety-like behavior is seen (J:241124)

hematopoietic system

microgliosis ( J:262453 )

♂ • 22 month old mice show a microglia response, particularly in major axonal tracts such as the corpus callosum

♂ • increases in microglia are seen in other brain regions including the cortex, striatum, hippocampus, and cerebellum

homeostasis/metabolism

increased ganglioside level ( J:229166 , J:241124 )

♂ • males show GM2 accumulation in neurons of hippocampal CA3/CA4 regions and amygdala at 4 weeks of age (J:229166)

♂ • GM2 ganglioside accumulation, particularly in the basolateral nuclei of the amygdala, occurs specifically in late endosomes and lysosomes (J:241124)

♂ • by 12 weeks of age, GM2 accumulation is also seen in neurons of CA3 and CA4 regions and the inner dentate gyrus of the hippocampus, as well as hypothalamus, fasciola cinereum, and piriform cortex (J:241124)

♂ • however, accumulation of GM1, GM3 or GD3 gangliosides in the brain is not seen (J:241124)

abnormal enzyme/coenzyme activity ( J:241124 )

♂ • no active beta-hexosaminidase enzyme activity, the lysosomal enzyme responsible for GM2 degradation, is seen in neurons storing GM2 ganglioside

immune system

microgliosis ( J:262453 )

♂ • 22 month old mice show a microglia response, particularly in major axonal tracts such as the corpus callosum

♂ • increases in microglia are seen in other brain regions including the cortex, striatum, hippocampus, and cerebellum

nervous system

abnormal brain morphology ( J:241124 )

♂ • small increase in hyperphosphorylated tau are seen in soluble brain fractions

decreased brain size ( J:262453 )

♂ • brain size is smaller at 2 years of age

decreased striatum size ( J:262453 )

♂ • striatal area is decreased at 22 months but not 2 months of age

abnormal amygdala morphology ( J:229166 , J:241124 )

♂ • a subpopulation of neurons in the amygdala lack specific lysosomal storage structures (J:229166)

♂ • GM2 ganglioside accumulation in late endosomes and lysosomes in the basolateral nuclei of the amygdala (J:241124)

abnormal cerebral hemisphere morphology ( J:262453 )

♂ • by 2 months of age, the cerebrum is smaller

♂ • cerebral brain volume shows an increase from P1 to 1 month, relative plateau at 1-2 months, slow growth but an increase at 2-6 months indicating delays in growth and a decrease at 6-23 months of age compared to wild-type mice which show an increase in volume at P0 to 1 month and 1-2 months, a plateau at 2-6 months, and decrease at 6-23 months, indicating undergrowth

abnormal hippocampus morphology ( J:262453 )

♂ • hippocampal area is decreased at 22 months but not 2 months of age

thin cerebral cortex ( J:262453 )

♂ • cortical thickness is decreased at 22 months but not 2 months

abnormal cerebellum morphology ( J:262453 )

♂ • cerebellar growth is similar to wild-type mice from P0 to 1 month, but mutants show decreased rate of increase from 1-2 months with a relative plateau from 2-6 months, and a severe decrease in cerebellar volume at a greater rate than the control from 6 to 23 months, indicating undergrowth from 0-6 months and significant neurodegeneration at 6-23 months in the cerebellum

Purkinje cell degeneration ( J:229166 , J:241124 , J:262453 )

♂ • neuron/dendritophagic clustering of CD68+ macrophages/microglia in the PC and molecular layers of cerebellar lobules I-II, III and VIII indicating Purkinje cell loss in these areas already at 4 weeks of age (J:229166)

♂ • cerebella shows extensive Purkinje cell loss in anterior and posterior zones at 32 weeks of age (J:229166)

♂ • extensive and progressive loss of Purkinje cells in the cerebellum (J:241124)

♂ • loss of Purkinje cells occurs in a regular pattern of parasagittal stripes in the cerebellar vermis and hemispheres (J:241124)

♂ • Purkinje cell loss occurs first within Zebrin II-negative stripes, while Zebrin II-postive stripes are more resistant, with Purkinje cells in lobules VI/VII and IX/X most resistant to degeneration (J:241124)

♂ • however, no cell loss is seen in the cerebrum (J:241124)

♂ • mice show progressive Purkinje cell loss in the primary fissure of the vermis largely starting after 2 months of age and worsening from 5 to 11-13 months (J:262453)

♂ • mice show decreased Purkinje cell density in the anterior lobe but not in the flocculonodular lobe at 5 and 11-13 months of age (J:262453)

abnormal Purkinje cell axon morphology ( J:241124 )

♂ • presence of Purkinje cell axonal spheroids

abnormal cerebellar molecular layer ( J:229166 )

♂ • atrophy and gliosis of the cerebellar molecular layer

small cerebellum ( J:262453 )

♂ • by 2 months of age, the cerebellum is smaller and remains smaller at 6 months and into old age

gliosis ( J:229166 )

♂ • gliosis in the cerebellar molecular layer

microgliosis ( J:262453 )

♂ • 22 month old mice show a microglia response, particularly in major axonal tracts such as the corpus callosum

♂ • increases in microglia are seen in other brain regions including the cortex, striatum, hippocampus, and cerebellum

astrocytosis ( J:262453 )

♂ • 22 month old mice show an astrocytic response, particularly in major axonal tracts such as the corpus callosum

♂ • increase in astrocytic response is also seen in the cerebellum and spinal cord

abnormal neuron morphology ( J:241124 )

♂ • increase in the number of lysosomes in neurons storing GM2 ganglioside

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
Christianson syndrome		DOID:0060825	OMIM:300243	J:229166 , J:241124 , J:262453

Genotype
MGI:3628583

ot4

• Allelic Composition: Slc9a6^tm1Dgen/Y
• Genetic Background: involves: 129P2/OlaHsd * C57BL/6

behavior/neurological

increased susceptibility to pharmacologically induced seizures ( J:101679 )

♂ • require a significantly lower dose of metrazol to reach various seizure states

increased locomotor activity ( J:101679 )

♂ • exhibit an increase in total distance traveled during open field testing

nervous system

increased susceptibility to pharmacologically induced seizures ( J:101679 )

♂ • require a significantly lower dose of metrazol to reach various seizure states