Phenotypes Associated with This Genotype

Genotype
MGI:8347734

• Allelic Composition: Hgsnat^em1Avps/Hgsnat^em1Avps
• Genetic Background: B6J(B6N)-Hgsnat^em1Avps

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

mortality/aging

premature death ( J:343336 )

• average lifespan in approximately 20 weeks less than that of Hgsnat ^{Gt(IST11912G1)Tigm} homozygotes

• most mice need to be euthanized by 45 weeks of age due to urinary retention

growth/size/body

weight loss ( J:343336 )

• mice show normal body weight gain but present with body weight loss at 7-8 months of age

enlarged kidney ( J:343336 )

• mice sacrificed at 40 weeks of age show enlargement of kidney

enlarged liver ( J:343336 )

• mice sacrificed at 40 weeks of age show enlargement of liver

hepatosplenomegaly ( J:343336 )

• mice sacrificed at 40 weeks of age show enlargement of liver and spleen

behavior/neurological

lethargy ( J:343336 )

• mice present with lethargy at 7-8 months of age

abnormal short-term spatial reference memory ( J:343336 )

• mice show deficits in spatial and short-term memory, with reduced recognition index in the novel object recognition test and reduced alternation rate in the Y-maze

• mice treated with glucosamine, an inhibitor of HGSNAT, show rescue of the memory deficit in the Y-maze

decreased anxiety-related response ( J:343336 )

• mice show reduced anxiety, showing increased distance traveled in the central part of the arena in the open field, and spending increased time in the open arms and increased number of open arm entries in the elevated plus maze at 4 months of age

decreased social novelty preference ( J:343336 )

• mice spend equal time exploring both familiar and novel objects or spend more time with a familiar object indicating a negative discrimination index

• mice treated with glucosamine show an increase in the discrimination index and the percentage of time spent with the novel object

hyperactivity ( J:343336 )

• mice show increased hyperactivity, traveling increased distance in the open field, at 4 months of age

cellular

astrocytosis ( J:343336 )

• levels of GFAP+ astrocytes at 4 months are increased in the hippocampus and in the somatosensory (layers 4-5) cortices

• glucosamine treatment does not change the severity of astromicrogliosis

microgliosis ( J:343336 )

• levels of activated CD68+ microglia at 4 months are increased in the hippocampus

abnormal lysosome morphology ( J:343336 )

• increase in levels of lysosomal biogenesis and lysosomal storage

• increase in levels of lysosome-associated membrane protein 2 (LAMP2)+ puncta in the somatosensory cortical pyramidal neurons in the brains of 4-month-old mice

• mice treated with glucosamine show reduction of LAMP+ puncta in cortical neurons

abnormal mitophagy ( J:343336 )

• neurons of cortical layer 4-5 stain heavily with antibodies against misfolded subunit C of mitochondrial ATP synthase at 6 months, suggestive of mitophagy block

• treatment with glucosamine reduces misfolded subunit C of mitochondrial ATP synthase aggregates in cortical neurons

impaired autophagy ( J:343336 )

• presence of LC3+ puncta is seen in cortical layer 4-5 pyramidal neurons at 6 months, suggesting an autophagy block

• somatosensory cortices (layers 4-5) show increased levels of makers of impaired autophagy and proteolysis, with increase is cytoplasmic LC3+ puncta, granular autofluorescent ceroid materials, amyloid beta-protein, and misfolded subunit C of mitochondrial ATP synthase at 6 months of age

increased endoplasmic reticulum stress ( J:343336 )

• brain shows increased levels of O-GlcNAc-modified proteins in the CA1 and cortical neurons, indicating ER stress associated with impaired cellular proteolysis

• cortices show increased levels of polyubiquitinated protein aggregates and an increased number of pyramidal neurons contain ubiquitin+ materials in somatosensory cortex layers 4 and 5, indicating increased levels of unfolded protein response in neurons

abnormal lysosome physiology ( J:343336 )

• neurons of cortical layer 4-5 contain increased levels of enlarged autofluorescent ceroid materials at 4 months, with increased number of cells containing the autoflurorescent material compared to that in Hgsnat ^{Gt(IST11912G1)Tigm} homozygotes, suggesting accelerated progression of this pathology

• treatment with glucosamine reduces autofluorescent ceroid material accumulation

hematopoietic system

microgliosis ( J:343336 )

• levels of activated CD68+ microglia at 4 months are increased in the hippocampus

hepatosplenomegaly ( J:343336 )

• mice sacrificed at 40 weeks of age show enlargement of liver and spleen

homeostasis/metabolism

abnormal mitophagy ( J:343336 )

• neurons of cortical layer 4-5 stain heavily with antibodies against misfolded subunit C of mitochondrial ATP synthase at 6 months, suggestive of mitophagy block

• treatment with glucosamine reduces misfolded subunit C of mitochondrial ATP synthase aggregates in cortical neurons

impaired autophagy ( J:343336 )

• presence of LC3+ puncta is seen in cortical layer 4-5 pyramidal neurons at 6 months, suggesting an autophagy block

• somatosensory cortices (layers 4-5) show increased levels of makers of impaired autophagy and proteolysis, with increase is cytoplasmic LC3+ puncta, granular autofluorescent ceroid materials, amyloid beta-protein, and misfolded subunit C of mitochondrial ATP synthase at 6 months of age

abnormal glycosaminoglycan level ( J:343336 )

• mice show increased levels of heparan sulfate-derived deltaDiHS-0S disaccharide in serum, urine, and brain and deltaDiHS-NS disaccharide in the brains indicating increased levels of glycosaminoglycan (GAG) storage

• mice treated with glucosamine show reduced levels of disaccharides produced by enzymatic digestion on heparan sulfate (deltaDiHS-0S and deltaDiHS-NS) in brain tissues

increased ganglioside level ( J:343336 )

• brain glycosphingolipid composition is altered, with more pronounced changes compared to Hgsnat ^{Gt(IST11912G1)Tigm} homozygotes, and with most drastic changes in the simple ganglioside GM3 levels

• 7-fold increase in GM3, 5-fold increase in GM2, and 3-fold increase in GA2 levels in the brain; levels show a trend for a progressive increase in these gangliosides with age

• treatment with glucosamine reduces GM2 ganglioside in pyramidal neurons of somatosensory cortex and CA1 area of the hippocampus

increased cytokine level ( J:343336 )

• brain shows increased expression levels of inflammatory cytokines MIP1alpha and TNFalpha

abnormal enzyme/coenzyme activity ( J:343336 )

• level of total beta-hyexosaminidase activity in the brain, liver, kidney, and lungs of 4-month-old mice is elevated

immune system

microgliosis ( J:343336 )

• levels of activated CD68+ microglia at 4 months are increased in the hippocampus

hepatosplenomegaly ( J:343336 )

• mice sacrificed at 40 weeks of age show enlargement of liver and spleen

increased cytokine level ( J:343336 )

• brain shows increased expression levels of inflammatory cytokines MIP1alpha and TNFalpha

liver/biliary system

enlarged liver ( J:343336 )

• mice sacrificed at 40 weeks of age show enlargement of liver

hepatosplenomegaly ( J:343336 )

• mice sacrificed at 40 weeks of age show enlargement of liver and spleen

nervous system

astrocytosis ( J:343336 )

• levels of GFAP+ astrocytes at 4 months are increased in the hippocampus and in the somatosensory (layers 4-5) cortices

• glucosamine treatment does not change the severity of astromicrogliosis

microgliosis ( J:343336 )

• levels of activated CD68+ microglia at 4 months are increased in the hippocampus

abnormal synapse morphology ( J:343336 )

• hippocampal neurons show a reduction in density of Syn1+ puncta along the MAP2-stained dendrites as well as of PSD95+ in juxtaposition with VGLUT1+ puncta

• the number of Gephyrin+/VGAT+ puncta in juxtaposition is reduced in neurons confirming that the GABAergic synapse is affected

• mice treated with glucosamine show a partial rescue of the excitatory synapse marker VGLUT1 and synaptic protein SYN1 in the hippocampal CA1 neurons, however PSD-95 levels are not restored

abnormal postsynaptic density morphology ( J:343336 )

• areas of excitatory postsynaptic densities (PSDs) of CA1 neurons are already reduced at 3 months of age and at 6 months, PSD areas are approximately 50% smaller than in wild-type mice

• PSD length of CA1 neurons is significantly reduced by 6 months compared to wild-type and Hgsnat ^{Gt(IST11912G1)Tigm} homozygous mice

• the density of synaptic vesicles in CA1 neurons shows a more rapid decrease than in Hgsnat ^{Gt(IST11912G1)Tigm} homozygotes, with a reduction by about 43% at 3 months and about 60% at 6 months

abnormal CNS synaptic transmission ( J:343336 )

• mice show more pronounced defects in neurotransmission and synaptic architecture compared with Hgsnat ^{Gt(IST11912G1)Tigm} homozygotes

decreased miniature excitatory postsynaptic current amplitude ( J:343336 )

• mice show an age-dependent decrease in miniature excitatory postsynaptic current (mEPSC) amplitudes (P14-P20 vs. P45-P60) suggesting progressive synaptic defects

• at P45-P60, mice show significantly reduced mEPSC frequencies compared to Hgsnat ^{Gt(IST11912G1)Tigm} mice

decreased miniature excitatory postsynaptic current frequency ( J:343336 )

• decrease in frequency of mEPSCs at P14-P20 and P45-P60

decreased miniature inhibitory postsynaptic current amplitude ( J:343336 )

• decrease in amplitude of mIPSCs at P14-P20 and P45-P60

decreased miniature inhibitory postsynaptic current frequency ( J:343336 )

• mice show aggravated defects in inhibitory neurotransmission, with reduced frequencies of miniature inhibitory postsynaptic currents (mIPSCs) at both P14-P40 and P45-P60 compared to wild-type and Hgsnat ^{Gt(IST11912G1)Tigm} mice

renal/urinary system

enlarged kidney ( J:343336 )

• mice sacrificed at 40 weeks of age show enlargement of kidney

ischuria ( J:343336 )

• mice present with urinary retention at 7-8 months of age mice resulting in abdominal distention

skeleton

skeleton phenotype ( J:343336 )

N • mice do not develop skeletal abnormalities

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
mucopolysaccharidosis type IIIC		DOID:0111393	OMIM:252930	J:343336