Phenotypes Associated with This Genotype

Genotype
MGI:5806128

• Allelic Composition: Hgsnat^{tm1a(EUCOMM)Wtsi}/Hgsnat^{tm1a(EUCOMM)Wtsi}
• Genetic Background: involves: C57BL/6N * C57BL/6NTac
• Cell Lines: EPD0485_4_B08

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

mortality/aging

premature death ( J:235361 )

• 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

increased blood urea nitrogen level ( J:235361 )

• at 12 and 22 months of age, homozygotes show a significant increase in serum urea levels, suggesting mild kidney damage

increased circulating alanine transaminase level ( J:235361 )

• at 12 months of age, homozygotes show a significant increase in serum ALT levels, suggesting mild liver damage

abnormal glycosaminoglycan level ( J:235361 )

• 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

abnormal enzyme/coenzyme activity ( J:235361 )

• 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

abnormal mitochondrial crista morphology ( J:235361 )

• at 5 months of age, Purkinje cell mitochondria show reduced cristae

abnormal Purkinje cell mitochondrial morphology ( J:235361 )

• at 5 months of age, Purkinje cell mitochondria display significant cristae loss and disorganization of the inner membrane system

abnormal lysosome morphology ( J:235361 )

• 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

abnormal nervous system morphology ( J:235361 )

• homozygotes display progressive storage disease in the CNS starting at an early age

abnormal cerebral cortex morphology ( J:235361 )

• 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

abnormal Purkinje cell morphology ( J:235361 )

• 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

abnormal Purkinje cell mitochondrial morphology ( J:235361 )

• at 5 months of age, Purkinje cell mitochondria display significant cristae loss and disorganization of the inner membrane system

abnormal CNS glial cell morphology ( J:235361 )

• at 5 months of age, perineuronal glial cells juxtaposed to cortical neurons display large intracytoplasmic vacuoles

microgliosis ( J:235361 )

• 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

astrocytosis ( J:235361 )

• 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

abnormal Kupffer cell morphology ( J:235361 )

• at 5 months of age, Kupffer cells exhibit a few but very distended storage vesicles

enlarged liver ( J:235361 )

• both sexes show hepatomegaly at 12 months of age or later

increased liver weight ( J:235361 )

• both sexes show increased liver weight at 12 months of age or later

abnormal hepatocyte morphology ( J:235361 )

• at 5 months of age, hepatocytes exhibit a large number of small electrolucent vacuoles in their cytoplasm

renal/urinary system

abnormal proximal convoluted tubule morphology ( J:235361 )

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

respiratory system

abnormal bronchus epithelium morphology ( J:235361 )

• 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

abnormal Kupffer cell morphology ( J:235361 )

• at 5 months of age, Kupffer cells exhibit a few but very distended storage vesicles

enlarged spleen ( J:235361 )

• both sexes show splenomegaly at 12 months of age or later

increased spleen weight ( J:235361 )

• both sexes show a progressive increase in spleen weight

microgliosis ( J:235361 )

• 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

cardiovascular system

abnormal Kupffer cell morphology ( J:235361 )

• at 5 months of age, Kupffer cells exhibit a few but very distended storage vesicles

abnormal ventricle myocardium morphology ( J:235361 )

• at 5 months of age, macrophage-like cells interspersed among myocardial cells of the cardiac ventricle display relatively large storage vesicles

behavior/neurological

increased anxiety-related response ( J:235361 )

♂ • 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

decreased locomotor activity ( J:235361 )

♂ • 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

abnormal Kupffer cell morphology ( J:235361 )

• at 5 months of age, Kupffer cells exhibit a few but very distended storage vesicles

enlarged spleen ( J:235361 )

• both sexes show splenomegaly at 12 months of age or later

increased spleen weight ( J:235361 )

• both sexes show a progressive increase in spleen weight

microgliosis ( J:235361 )

• 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

muscle

abnormal ventricle myocardium morphology ( J:235361 )

• at 5 months of age, macrophage-like cells interspersed among myocardial cells of the cardiac ventricle display relatively large storage vesicles

growth/size/body

enlarged liver ( J:235361 )

• both sexes show hepatomegaly at 12 months of age or later

increased liver weight ( J:235361 )

• both sexes show increased liver weight at 12 months of age or later

enlarged spleen ( J:235361 )

• both sexes show splenomegaly at 12 months of age or later

increased spleen weight ( J:235361 )

• 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