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Phenotypes Associated with This Genotype
Genotype
MGI:5806128
Allelic
Composition
Hgsnattm1a(EUCOMM)Wtsi/Hgsnattm1a(EUCOMM)Wtsi
Genetic
Background
involves: C57BL/6N * C57BL/6NTac
Cell Lines EPD0485_4_B08
Find Mice Using the International Mouse Strain Resource (IMSR)
Mouse lines carrying:
Hgsnattm1a(EUCOMM)Wtsi mutation (0 available); any Hgsnat mutation (10 available)
phenotype observed in females
phenotype observed in males
N normal phenotype
muscle
• at 5 months of age, macrophage-like cells interspersed among myocardial cells of the cardiac ventricle display relatively large storage vesicles

mortality/aging
• male homozygotes have a median survival of 21.2 months relative to 24.6 months for wild-type males
• female homozygotes have a median survival of 19.7 months relative to 23 months for wild-type females

homeostasis/metabolism
• at 12 and 22 months of age, homozygotes show a significant increase in serum urea levels, suggesting mild kidney damage
• at 12 months of age, homozygotes show a significant increase in serum ALT levels, suggesting mild liver damage
• both sexes show a progressive increase in GAG accumulation in all brain regions analyzed, ranging from 4% to 80% over values detected in healthy littermates
• accumulation is highly prominent in the most frontal portions of the brain, where excessive GAG storage is detected as early as 2 months of age
• both sexes show progressive accumulation of GAGs in most somatic organs analyzed as early as 2 months of age, with a substantial increase between 2 and 12 months of age
• in somatic organs, build-up of undegraded GAGs is most prominent in liver, spleen and kidney
• brain extracts from homozygotes show altered activities of several lysosomal enzymes, including iduronate-2-sulfatase (IDS), N-sulphoglucosamine sulphohydrolase (SGSH), alpha-N-acetylglucosaminidase (NAGLU), N-acetylgalactosamine-6-sulfatase (GALNS), beta-glucuronidase (GUSB) and beta-hexosaminidase (beta-HEXO)
• altered brain enzymatic activities are detected as early as 2 months of age and persist until 22 months of age
• similar to brain, liver extracts show altered activities of iduronidase (IDUA), IDS, SGSH, NAGLU, GALNS, GUSB, and beta-HEXO, indicating a general alteration of lysosomal homeostasis
• in most cases, the activity of these enzymes is increased by several fold from an early age, with the strongest increase observed for beta-HEXO; of these, only GALNS activity is decreased in brain and liver extracts

cellular
• at 5 months of age, Purkinje cell mitochondria display loss of normal mitochondrial structure
• at 5 months of age, Purkinje cell mitochondria show disorganization of the inner membrane and reduced cristae
• as early as 2 months of age, both sexes show a progressive increase in LAMP2+ area and signal intensity in all CNS regions analyzed, suggesting that distension of the CNS lysosomal compartment worsens with age
• TEM confirmed increase in the size of the lysosomal compartment in the cerebral cortex and cerebellum
• both sexes show a progressive enlargement of the lysosomal compartment in the liver, heart, lung and urinary bladder
• pattern of enlargement of the lysosomal compartment varies depending on the cell type and organ

nervous system
• homozygotes display progressive storage disease in the CNS starting at an early age
• at 5 months of age, large electrolucent vacuoles that appear to be lysosomes loaded with GAGs are noted in the cytoplasm of perineuronal glial cells apposed to neurons of the cerebral cortex
• at 5 months of age, electrolucent vesicles of smaller size are found in the cytoplasm of cerebellar Purkinje cells with a seemingly different content than that observed in cortical perineuronal glial cells
• Purkinje cell mitochondria display significant cristae loss and disorganization of the inner membrane system
• at 5 months of age, perineuronal glial cells juxtaposed to cortical neurons display large intracytoplasmic vacuoles
• both sexes exhibit progressive infiltration with activated microglia in all brain regions analyzed as early as 2 months of age
• increase in % BSI-B4+ area remains significant at 12 and 22 months of age in all brain regions
• both sexes exhibit significant astrocytosis in all brain regions analyzed as early as 2 months of age
• increase in % GFAP+ area remains significant at 12 and 22 months of age in all brain regions (frontal cortex, parietal cortex, occipital cortex, and thalamus), except for the superior colliculus where significance is lost by 22 months of age

liver/biliary system
• at 5 months of age, Kupffer cells exhibit a few but very distended storage vesicles
• at 5 months of age, hepatocytes exhibit a large number of small electrolucent vacuoles in their cytoplasm
• both sexes show hepatomegaly at 12 months of age or later
• both sexes show increased liver weight at 12 months of age or later

renal/urinary system
• at 5 months of age, proximal tubule cells display storage vesicles of a size similar to that seen in hepatocytes

respiratory system
• at 5 months of age, ciliated cells from the bronchial tube of the lung display relatively large storage vesicles whereas exocrine club cells do not

hematopoietic system
• at 5 months of age, Kupffer cells exhibit a few but very distended storage vesicles
• both sexes exhibit progressive infiltration with activated microglia in all brain regions analyzed as early as 2 months of age
• increase in % BSI-B4+ area remains significant at 12 and 22 months of age in all brain regions
• both sexes show splenomegaly at 12 months of age or later
• both sexes show a progressive increase in spleen weight

cardiovascular system
• at 5 months of age, Kupffer cells exhibit a few but very distended storage vesicles
• at 5 months of age, macrophage-like cells interspersed among myocardial cells of the cardiac ventricle display relatively large storage vesicles

behavior/neurological
• in the open field test, 28.5% of 2-month-old homozygotes fail to enter the center of the arena in the first 3 min relative to 0% of wild-type controls
• at 12 and 22 months of age, the % of homozygotes taking >3 min to enter the center of the arena for the first time increases to 34% and 68.4%, respectively; in contrast, only one wild-type mouse failed to visit the center during the first 3 min at 12 months, increasing to 25% at 22 months
• at 2, 12 and 22 months of age, homozygotes cross fewer lines and travel less distance than wild-type controls during the first 3 minutes of an open filed assay, and spend more time resting, suggesting hypoactivity
• behavioral analysis over a 15 min period revealed that younger homozygotes show identical behavior to wild-type controls, whereas older homozygotes remain hypoactive, indicating loss of motor functions

immune system
• at 5 months of age, Kupffer cells exhibit a few but very distended storage vesicles
• both sexes exhibit progressive infiltration with activated microglia in all brain regions analyzed as early as 2 months of age
• increase in % BSI-B4+ area remains significant at 12 and 22 months of age in all brain regions
• both sexes show splenomegaly at 12 months of age or later
• both sexes show a progressive increase in spleen weight

Mouse Models of Human Disease
DO ID OMIM ID(s) Ref(s)
mucopolysaccharidosis III DOID:12801 OMIM:252940
J:235361


Contributing Projects:
Mouse Genome Database (MGD), Gene Expression Database (GXD), Mouse Models of Human Cancer database (MMHCdb) (formerly Mouse Tumor Biology (MTB), Gene Ontology (GO)
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last database update
05/19/2020
MGI 6.15
The Jackson Laboratory