Mouse Genome Informatics
hm1
    Naglutm1Efn/Naglutm1Efn
either: (involves: 129S/SvEv * C57BL/6) or (involves: C57BL/6)
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype

Abnormal inclusions in tissues of Naglutm1Efn/Naglutm1Efn mice

mortality/aging
• homozygotes survive to 8-12 months
• appear normal, healthy, and fertile up to 6 months of age

behavior/neurological
• suppressed open field activity in mice over 4.5 months of age
• older mice demonstrate a reduced freezing response to the tone used in fear tests
• difficulty walking after about 6 months of age

growth/size
• weight loss starts to occur at some time after 6 months of age
• after 6 months of age

hematopoietic system
• by 33 days of age, vacuolated macrophages are found in many organs
• vacuolated macrophages become more widely distributed with age to 6 months
• Kupffer cells are ballooned and contain very few large inclusions

immune system
• by 33 days of age, vacuolated macrophages are found in many organs
• vacuolated macrophages become more widely distributed with age to 6 months
• Kupffer cells are ballooned and contain very few large inclusions

liver/biliary system
• Kupffer cells are ballooned and contain very few large inclusions
• hepatocytes contain many large vacuoles

renal/urinary system
• vacuolated glomerular epithelial cells seen by 33 days of age
• extent of vacuolation increases with age to at least 6 months
• by 33 days of age, epithelial cells are vacuolated in distal but not proximal convoluted tubules, and in Henle's loop
• at 3 to 6 months of age, more prominent vacuolation is seen in tubular epithelial cells as well as interstitial cells
• however, mesangial cells are not vacuolated
• urinary retention in the bladder starting at 6 months of age

nervous system
• some vacuolated neurons
• neurons in the thalamus and the hypothalamus with vacuoles
• some vacuolated neurons
• some areas of the cortex contain vacuolated neurons
• accessory olfactory bulb with vacuolated neurons
• olfactory bulb with vacuolated neurons
• neurons of cerebellar nuclei containing one or more inclusions similar to those found in Purkinje cells
• by 33 days of age, some neurons in various regions of the brain become vacuolated
• extent of vacuolation increases with age
• rather than vacuoles cells may contain one or more large periodic acid/Schiff positive inclusions

cardiovascular system
• Kupffer cells are ballooned and contain very few large inclusions

integument
• after 6 months of age
• skin ulceration around the genitalia occurs after 6 months of age

Mouse Models of Human Disease
OMIM IDRef(s)
Mucopolysaccharidosis, Type IIIB; MPS3B 252920 J:58950


Mouse Genome Informatics
hm2
    Naglutm1Efn/Naglutm1Efn
involves: 129S/SvEv * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype

Electron microscopic examination of the cortex of a Naglutm1Efn/Naglutm1Efn mouse

nervous system
• vacuolated microglial cells sometimes apposed to neurons

Mouse Models of Human Disease
OMIM IDRef(s)
Mucopolysaccharidosis, Type IIIB; MPS3B 252920 J:81974


Mouse Genome Informatics
hm3
    Naglutm1Efn/Naglutm1Efn
involves: 129S/SvEv * C57BL/6J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype

Middle ear abnormalities in Naglutm1Efn/Naglutm1Efn mice at 30 weeks of age

mortality/aging
• average age of death is 315-360 days

cellular
• mutants exhibit lysosomal distention in multiple tissues, including in the middle and inner ear, in the eye, and in the suprachiasmatic nucleus

behavior/neurological
• percentage of daily activity which occurs during the light portion of the LD cycle is increased in mutants
• mutants differ from wild-type in their phase angle of entrainment (the time from the light offset to the onset of daily locomotor activity); mutants start their daily activity about 1 hour later than wild-type
• rotarod testing shows a progressive inability of older, but not younger, mutants to coordinate movement in a rocking paradigm

nervous system
• complete loss of hair cells in the lower base coincides with degeneration of the organ of Corti
• the suprachiasmatic nucleus (SCN) shows a large number of pyknotic cells with condensed nuclei and cytoplasms and distended lysosomes
• age dependent loss of Purkinje cells
• diffuse decrease in cerebellar Purkinje neuronal counts at the vermis in older, but not younger, mutants
• progressive shortening of the outer segments

hearing/vestibular/ear
• inflammatory cells are more likely to appear in the perilymphatic scalae of mutants than wild-type and often show lysosomal storage
• lysosomal storage is seen in Reissner's membrane
• lysosomal storage in the organ of Corti occurs within outer sulcus cells of the lateral organ and pillar cells of the medial organ
• complete loss of hair cells in the lower base coincides with degeneration of the organ of Corti
• lysosomal storage is seen in the spiral ligament
• lysosomal storage is seen in the spiral limbus
• abnormal lysosomal storage in the crista ampullaris of the lateral semicircular canal
• the vestibular maculae and cristae show prominent lysosome storage in both supporting cells and hair cells and the dark cells of the cristae
• middle ears at 30 weeks of age show lysosomal storage-related anomalies
• lysosomal storage is prominent in the mucosal lining and within osteocytes, chondrocytes, and inflammatory cells
• thickened mucosal layer on stapes and malleus at 30 weeks of age with hyperplasia of mucosal cells
• bone surface of the stapes is pitted, indicating abnormal bone remodeling
• increase in high frequency ABR thresholds is significantly greater in mutants up to 16 weeks than in controls
• auditory brainstem response (ABR) shows progressive hearing deficits
• middle ears at 30 weeks of age exhibit highly variable otitis media, with and without effusion

vision/eye
• aberrant lysosomal storage is seen in the inner retina
• progressive shortening of the outer segments
• localized disruption and inclusions in the retinal pigment epithelium
• progressive reduction of the outer nuclear layer
• lysosomal storage in the sclera
• ERG shows a progressive decrease in the amplitude of the dark-adapted b-wave response
• dark-adapted retinal response is depressed by 5 weeks and becomes progressively less sensitive with increasing age, indicating loss of rod function
• however, cone function appears normal

immune system
• middle ears at 30 weeks of age exhibit highly variable otitis media, with and without effusion

craniofacial
• thickened mucosal layer on stapes and malleus at 30 weeks of age with hyperplasia of mucosal cells
• bone surface of the stapes is pitted, indicating abnormal bone remodeling

pigmentation
• localized disruption and inclusions in the retinal pigment epithelium

skeleton
• thickened mucosal layer on stapes and malleus at 30 weeks of age with hyperplasia of mucosal cells
• bone surface of the stapes is pitted, indicating abnormal bone remodeling
• lysosomal storage is seen in the spiral ligament