Overview

Also Known As:Naglu-

These Naglu knock-out mice exhibit massive accumulation of heparan sulfate in liver and kidney and vacuolation in many cells, including macrophages, epithelial cells, and neurons.

Donating Investigator

Elizabeth F. Neufeld, UCLA School of Medicine

Genetic overview

Genetic Background	Generation

Naglu^tm1Efn

Allele Type	Gene Symbol	Gene Name
Targeted (Null/Knockout)	Naglu	alpha-N-acetylglucosaminidase (Sanfilippo disease IIIB)

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Research Applications

Mouse/Human Gene Homologs

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Base Price

Starting at:

$2,854.50 Domestic price Cryo Recovery

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Details

Detailed Description

At birth, homozygous null mice are viable, normal in size, and do not display any gross physical or behavioral abnormalities. The lysosomal enzyme alpha-N-acetylglucosaminidase (Naglu) is absent in all tissues. Large amounts of heparan sulfate accumulate in liver and kidney, and lesser amounts in other organs. At one month of age, vacuolated macrophages can be found in most tissues. Epithelial cells in kidney and neurons in some parts of the brain are also affected. The vacuolation becomes more prominent with age. At 4-5 months, the mice show abnormal behavior in an open field test. The life span is 8-12 months. Older animals may have urinary retention and difficulty walking and must be euthanized. The null mice were originally described as fertile, but their fertility has decreasd markedly with repeated back-crossing to an inbred strain. These mice are suitable for examining the pathophysiology of the Sanfilippo syndrome type B and for developing therapies for this lysosomal storage disorder.

Development

A targeting vector containing a neomycin resistance gene driven by the mouse phosphoglycerate kinase promoter and a Herpes simplex virus thymidine kinase gene driven by its own promoter was used to disrupt a portion of exon 6. The construct was electroporated into 129S6/SvEv-derived CCE embryonic stem (ES) cells. Correctly targeted ES cells were injected into C57BL/6 blastocysts. The resulting chimeric male animals were backcrossed to C57BL/6 females.

Control Suggestions

Wild-type from the colony
000664 C57BL/6J

Additional Information

Considerations for Choosing Controls

Genetics

Naglu^tm1Efn

Allele Symbol: Naglu^tm1Efn

Allele Name	targeted mutation 1, Elizabeth F Neufeld
Allele Type	Targeted (Null/Knockout)
Allele Synonym(s)	MPS IIIB; Naglu-
Gene Symbol and Name	Naglu, alpha-N-acetylglucosaminidase (Sanfilippo disease IIIB)
Gene Synonym(s)
Strain of Origin	129S/SvEv-Gpi1^c
Chromosome	11
Molecular Note	Exon 6 of this gene, a region known to harbor several Sanfilippo B mutations, was disrupted by the insertion of a neomycin resistance gene via homologous recombination. Protein from homozygous mutant animals was negative for enzyme activity.
Mutations Made By	Elizabeth Neufeld, UCLA School of Medicine

Disease/Phenotype

Disease Terms

Model with phenotypic similarity to human disease where etiologies involve orthologs. Human genes are associated with this disease. Orthologs of those genes appear in the mouse genotype(s).

mucopolysaccharidosis III

Model with phenotypic similarity to human disease where etiologies are distinct. Human genes are associated with this disease. Orthologs of these genes do not appear in the mouse genotype(s).

otitis media

Research Areas By Phenotype

This mouse can be used to support research in many areas including:

Genotype: Naglu^tm1Efn related

Mouse/Human Gene Homologs
- mucopolysaccharidosis III B, Sanfilippo syndrome B

Mammalian Phenotype Terms by Genotype

The following phenotype information is associated with a similar, but not exact match to this JAX^® Mice strain

Genotype: Naglu^tm1Efn/Naglu^tm1Efn
involves: 129S/SvEv * C57BL/6

nervous system phenotype

abnormal cerebral cortex morphology
- vacuolated microglial cells sometimes apposed to neurons

The following phenotype relates to a compound genotype created using this strain

Genotype: Naglu^tm1Efn/Naglu^tm1Efn
involves: 129S/SvEv * C57BL/6J

behavior/neurological phenotype

abnormal circadian behavior
- percentage of daily activity which occurs during the light portion of the LD cycle is increased in mutants

delayed circadian behavior phase
- 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

impaired coordination
- rotarod testing shows a progressive inability of older, but not younger, mutants to coordinate movement in a rocking paradigm

hearing/vestibular/ear phenotype

abnormal middle ear morphology
- 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

increased or absent threshold for auditory brainstem response
- increase in high frequency ABR thresholds is significantly greater in mutants up to 16 weeks than in controls

increased susceptibility to otitis media
- middle ears at 30 weeks of age exhibit highly variable otitis media, with and without effusion

abnormal spiral ligament morphology
- lysosomal storage is seen in the spiral ligament

organ of Corti degeneration

abnormal cochlea morphology
- inflammatory cells are more likely to appear in the perilymphatic scalae of mutants than wild-type and often show lysosomal storage

abnormal organ of Corti morphology
- lysosomal storage in the organ of Corti occurs within outer sulcus cells of the lateral organ and pillar cells of the medial organ

abnormal spiral limbus morphology
- lysosomal storage is seen in the spiral limbus

conductive hearing loss
- auditory brainstem response (ABR) shows progressive hearing deficits

abnormal crista ampullaris morphology
- abnormal lysosomal storage in the crista ampullaris of the lateral semicircular canal

abnormal inner ear vestibule morphology
- the vestibular maculae and cristae show prominent lysosome storage in both supporting cells and hair cells and the dark cells of the cristae

abnormal inner ear morphology

decreased cochlear hair cell number
- complete loss of hair cells in the lower base coincides with degeneration of the organ of Corti

abnormal middle ear ossicle morphology
- thickened mucosal layer on stapes and malleus at 30 weeks of age with hyperplasia of mucosal cells

abnormal Reissner membrane morphology
- lysosomal storage is seen in Reissner's membrane

abnormal stapes morphology
- bone surface of the stapes is pitted, indicating abnormal bone remodeling

immune system phenotype

increased susceptibility to otitis media
- middle ears at 30 weeks of age exhibit highly variable otitis media, with and without effusion

mortality/aging

premature death
- average age of death is 315-360 days

nervous system phenotype

decreased cochlear hair cell number
- complete loss of hair cells in the lower base coincides with degeneration of the organ of Corti

decreased Purkinje cell number
- diffuse decrease in cerebellar Purkinje neuronal counts at the vermis in older, but not younger, mutants

abnormal suprachiasmatic nucleus morphology
- the suprachiasmatic nucleus (SCN) shows a large number of pyknotic cells with condensed nuclei and cytoplasms and distended lysosomes

Purkinje cell degeneration
- age dependent loss of Purkinje cells

short photoreceptor outer segment
- progressive shortening of the outer segments

pigmentation phenotype

abnormal retinal pigment epithelium morphology
- localized disruption and inclusions in the retinal pigment epithelium

skeleton phenotype

abnormal spiral ligament morphology
- lysosomal storage is seen in the spiral ligament

abnormal middle ear ossicle morphology
- thickened mucosal layer on stapes and malleus at 30 weeks of age with hyperplasia of mucosal cells

abnormal stapes morphology
- bone surface of the stapes is pitted, indicating abnormal bone remodeling

vision/eye phenotype

abnormal retinal pigment epithelium morphology
- localized disruption and inclusions in the retinal pigment epithelium

abnormal eye electrophysiology
- ERG shows a progressive decrease in the amplitude of the dark-adapted b-wave response

abnormal retina morphology
- aberrant lysosomal storage is seen in the inner retina

abnormal rod electrophysiology
- dark-adapted retinal response is depressed by 5 weeks and becomes progressively less sensitive with increasing age, indicating loss of rod function
- Normal - however, cone function appears normal

abnormal sclera morphology
- lysosomal storage in the sclera

short photoreceptor outer segment
- progressive shortening of the outer segments

thin retinal outer nuclear layer
- progressive reduction of the outer nuclear layer

cellular phenotype

abnormal lysosome morphology
- mutants exhibit lysosomal distention in multiple tissues, including in the middle and inner ear, in the eye, and in the suprachiasmatic nucleus

craniofacial phenotype

abnormal stapes morphology
- bone surface of the stapes is pitted, indicating abnormal bone remodeling

abnormal middle ear ossicle morphology
- thickened mucosal layer on stapes and malleus at 30 weeks of age with hyperplasia of mucosal cells

Genotype: Naglu^tm1Efn/Naglu^tm1Efn
either: (involves: 129S/SvEv * C57BL/6) or (involves: C57BL/6)

immune system phenotype

abnormal macrophage morphology
- by 33 days of age, vacuolated macrophages are found in many organs
- vacuolated macrophages become more widely distributed with age to 6 months

abnormal Kupffer cell morphology
- Kupffer cells are ballooned and contain very few large inclusions

integument phenotype

disheveled coat
- after 6 months of age

spontaneous skin ulceration
- skin ulceration around the genitalia occurs after 6 months of age

liver/biliary system phenotype

abnormal hepatocyte morphology
- hepatocytes contain many large vacuoles

abnormal Kupffer cell morphology
- Kupffer cells are ballooned and contain very few large inclusions

mortality/aging

premature death
- homozygotes survive to 8-12 months
- appear normal, healthy, and fertile up to 6 months of age

nervous system phenotype

abnormal neuron morphology
- extent of vacuolation increases with age
- by 33 days of age, some neurons in various regions of the brain become vacuolated

abnormal accessory olfactory bulb morphology
- accessory olfactory bulb with vacuolated neurons

abnormal amygdala morphology
- some vacuolated neurons

abnormal cerebellum deep nucleus morphology
- neurons of cerebellar nuclei containing one or more inclusions similar to those found in Purkinje cells

abnormal diencephalon morphology
- neurons in the thalamus and the hypothalamus with vacuoles

abnormal pons morphology
- some vacuolated neurons

abnormal cerebral cortex morphology
- some areas of the cortex contain vacuolated neurons

abnormal midbrain morphology

abnormal Purkinje cell morphology
- rather than vacuoles cells may contain one or more large periodic acid/Schiff positive inclusions

abnormal olfactory bulb morphology
- olfactory bulb with vacuolated neurons

behavior/neurological phenotype

increased anxiety-related response
- suppressed open field activity in mice over 4.5 months of age

abnormal locomotor behavior
- difficulty walking after about 6 months of age

decreased fear-related response
- older mice demonstrate a reduced freezing response to the tone used in fear tests

renal/urinary system phenotype

abnormal podocyte morphology
- vacuolated glomerular epithelial cells seen by 33 days of age
- extent of vacuolation increases with age to at least 6 months

ischuria
- urinary retention in the bladder starting at 6 months of age

abnormal renal tubule epithelium morphology
- at 3 to 6 months of age, more prominent vacuolation is seen in tubular epithelial cells as well as interstitial cells
- Normal - however, mesangial cells are not vacuolated
- by 33 days of age, epithelial cells are vacuolated in distal but not proximal convoluted tubules, and in Henle's loop

cardiovascular system phenotype

abnormal Kupffer cell morphology
- Kupffer cells are ballooned and contain very few large inclusions

growth/size/body region phenotype

distended abdomen
- after 6 months of age

weight loss
- weight loss starts to occur at some time after 6 months of age

hematopoietic system phenotype

abnormal macrophage morphology
- by 33 days of age, vacuolated macrophages are found in many organs
- vacuolated macrophages become more widely distributed with age to 6 months

abnormal Kupffer cell morphology
- Kupffer cells are ballooned and contain very few large inclusions

References

Additional References

Gografe SI; Garbuzova-Davis S; Willing AE; Haas K; Chamizo W; Sanberg PR. 2003. Mouse model of Sanfilippo syndrome type B: relation of phenotypic features to background strain. Comp Med 53(6):622-32PubMed: 14727810 MGI: J:87310

Additional - Naglu^tm1Efn related

Technical Support

CONTACT TECHNICAL SUPPORT

Genotyping Protocols
- Standard PCR:Naglu
- Genotyping resources and troubleshooting
Breeding Considerations

This strain originated on a B6;129S6 background and has been backcrossed to C57BL/6J for ten generations(9/2000). The donating investigator maintains this mutant strain by backcrossing to C57BL/6 animals. Coat color expeced from breeding:Black
- Additional Breeding and Husbandry Support
Citation
When using the Naglu- mouse strain in a publication, please cite the originating article(s) and include JAX stock #003827 in your Materials and Methods section.

Animal Health Reports

Facility Barrier Level Descriptions

Production of mice from cryopreserved embryos or sperm occurs in a maximum barrier room, G200

Pricing & Availability

Cryo Recovery

Domestic
International

Live Mouse

Age

Genotype

Price

weeks

Cryorecovery - Pricing

Service/Product	Description	Price
> >	Heterozygous for Naglu<tm1Efn>

Payment Terms and Conditions

Terms are granted by individual review and stated on the customer invoice(s) and account statement. These transactions are payable in U.S. currency within the granted terms. Payment for services, products, shipping containers, and shipping costs that are rendered are expected within the payment terms indicated on the invoice or stated by contract. Invoices and account balances in arrears of stated terms may result in The Jackson Laboratory pursuing collection activities including but not limited to outside agencies and court filings.

The Jackson Laboratory's Genotype Promise

The Jackson Laboratory has rigorous genetic quality control and mutant gene genotyping programs to ensure the genetic background of JAX® Mice strains as well as the genotypes of strains with identified molecular mutations. JAX® Mice strains are only made available to researchers after meeting our standards. However, the phenotype of each strain may not be fully characterized and/or captured in the strain data sheets. Therefore, we cannot guarantee a strain's phenotype will meet all expectations. To ensure that JAX® Mice will meet the needs of individual research projects or when requesting a strain that is new to your research, we suggest ordering and performing tests on a small number of mice to determine suitability for your particular project. We do not guarantee breeding performance and therefore suggest that investigators order more than one breeding pair to avoid delays in their research.

Terms Of Use

General Terms and Conditions

Questions about Terms of Use

Licensing Information

Phone: 207-288-6470

Email: TechTran@jax.org

Also Known As:Naglu-

Donating Investigator

Genetic overview

Research Applications

Base Price

Detailed Description

Development

Control Suggestions

Additional Information

Naglutm1Efn

Allele Symbol: Naglutm1Efn

Disease Terms

Model with phenotypic similarity to human disease where etiologies involve orthologs. Human genes are associated with this disease. Orthologs of those genes appear in the mouse genotype(s).

Model with phenotypic similarity to human disease where etiologies are distinct. Human genes are associated with this disease. Orthologs of these genes do not appear in the mouse genotype(s).

Research Areas By Phenotype

This mouse can be used to support research in many areas including:

Genotype: Naglutm1Efn related

Mammalian Phenotype Terms by Genotype

Genotype: Naglutm1Efn/Naglutm1Efninvolves: 129S/SvEv * C57BL/6

nervous system phenotype

Genotype: Naglutm1Efn/Naglutm1Efninvolves: 129S/SvEv * C57BL/6J

behavior/neurological phenotype

hearing/vestibular/ear phenotype

immune system phenotype

mortality/aging

nervous system phenotype

pigmentation phenotype

skeleton phenotype

vision/eye phenotype

cellular phenotype

craniofacial phenotype

Genotype: Naglutm1Efn/Naglutm1Efneither: (involves: 129S/SvEv * C57BL/6) or (involves: C57BL/6)

immune system phenotype

integument phenotype

liver/biliary system phenotype

mortality/aging

nervous system phenotype

behavior/neurological phenotype

renal/urinary system phenotype

cardiovascular system phenotype

growth/size/body region phenotype

hematopoietic system phenotype

References

Additional References

Additional - Naglutm1Efn related

Genotyping Protocols

Breeding Considerations

Citation

Animal Health Reports

Production of mice from cryopreserved embryos or sperm occurs in a maximum barrier room, G200

Live Mouse

Cryorecovery - Pricing

Payment Terms and Conditions

The Jackson Laboratory's Genotype Promise

Terms Of Use

Licensing Information

Naglu^tm1Efn

Allele Symbol: Naglu^tm1Efn

Genotype: Naglu^tm1Efn related

Genotype: Naglu^tm1Efn/Naglu^tm1Efn
involves: 129S/SvEv * C57BL/6

Genotype: Naglu^tm1Efn/Naglu^tm1Efn
involves: 129S/SvEv * C57BL/6J

Genotype: Naglu^tm1Efn/Naglu^tm1Efn
either: (involves: 129S/SvEv * C57BL/6) or (involves: C57BL/6)

Additional - Naglu^tm1Efn related