Description

The genotypes of the animals provided may not reflect those discussed in the strain description or the mating scheme utilized by The Jackson Laboratory prior to cryopreservation. Please inquire for possible genotypes for this specific strain.

Strain Information

Type Congenic; Mutant Strain; Targeted Mutation; Additional information on Genetically Engineered and Mutant Mice. Visit our online Nomenclature tutorial. Additional information on Congenic nomenclature. Species laboratory mouse   Donating Investigator Daniel R. McMillan,   UT Southwestern Medical Center

Description
Mice that are homozygous for the targeted mutation are viable, fertile, normal in size and do not display any gross physical abnormalities. A mutant gene product (protein) is detected by Western blot analysis of embryos. High-intensity sound induces audiogenic seizures that often results in death. Cochlear hair cell stereociliary bundles are do not mature properly, lack ankle links and are disorganized. Hair cells and pillar cells in the basal half of the cochlea degenerate and are lost by 2 months of age. Homozygotes become profoundly deaf by 3 weeks of age. Electroretinographic analysis reveals abnormal light-adapted cone-only responses. Mutant mice exhibit abnormal retinal photoreceptor cells ultrastructure and age-related vision loss. This mutant mouse strain may be useful in studies of Usher syndrome type IIC, cochlear development, deafness and blindness.

Development
A targeting vector containing neomycin resistance and herpes simplex virus thymidine kinase genes and a HA tag, a 6xHis affinity purification tag and a translational stop codon was used to disrupt 101 bp of exon 82. The construct was electroporated into 129S1/Sv-Oca2⁺ Tyr⁺ Kitl⁺ derived CJ7 embryonic stem (ES) cells. Correctly targeted ES cells were injected into recipient blastocysts. The resulting chimeric animals were crossed to C57BL/6J mice, and then backcrossed to C57BL/6J for 11 generations.

Control Information

	Control
	000664 C57BL/6J
Considerations for Choosing Controls

Phenotype

Phenotype Information

View Related Disease (OMIM) Terms

Related Disease (OMIM) Terms provided by MGI

- 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).

Usher Syndrome, Type IIC; USH2C

- Potential model based on gene homology relationships. Phenotypic similarity to the human disease has not been tested. Febrile Seizures, Familial, 4; FEB4   (GPR98)

View Mammalian Phenotype Terms

Mammalian Phenotype Terms provided by MGI

      assigned by genotype

The following phenotype information may relate to a genetic background differing from this JAX^® Mice strain.

Gpr98^tm1Pwh/Gpr98^tm1Pwh

        involves: 129S1/Sv * C57BL/6J

• mortality/aging
• increased sensitivity to induced morbidity/mortality
  • without intervention audiogenic seizures frequently result in death as a result of respiratory distress   (MGI Ref ID J:90899)
• behavior/neurological phenotype
• audiogenic seizures
  • a high intensity sound stimulus triggers audiogenic seizures that frequently continue to full tonic-clonic extension   (MGI Ref ID J:90899)
• hearing/vestibular/ear phenotype
• abnormal cochlear hair cell stereociliary bundle morphology
  • by P2, homozygotes exhibit a disorganized cochlear hair bundle morphology, which is more prominent at P4   (MGI Ref ID J:109595)
  • no further exacerbation of hair bundle morphology occurs with increasing age, as determined at P28   (MGI Ref ID J:109595)
• • abnormal inner hair cell stereociliary bundle morphology   (MGI Ref ID J:109595)
  • abnormal outer hair cell stereociliary bundle morphology
    • at P2, many of the homozygous mutant OHC stereociliary bundles in apical coils display a less sharply defined V-shape relative to those in heterozygous OHCs   (MGI Ref ID J:109595)
    • by P4, mutant OHC stereociliary bundles display a more rounded shape and lack bilateral symmetry   (MGI Ref ID J:109595)
  • • abnormal orientation of outer hair cell stereociliary bundles
      • by P4, mutant OHC stereociliary bundles exhibit a degree of disorientation   (MGI Ref ID J:109595)
  • absent cochlear hair bundle ankle links
    • at P2, ankle links are absent from both cochlear inner and outer hair cell stereociliary bundles   (MGI Ref ID J:109595)
    • surprisingly, ankle links in mutant vestibular hair cell stereociliary bundles appear unaffected   (MGI Ref ID J:109595)
• abnormal cochlear outer hair cell physiology
  • single-cell recordings show that most cochlear OHCs fail to respond to fairly large hair bundle displacements by P7   (MGI Ref ID J:109595)
• abnormal hair cell mechanoelectric transduction
  • FM1-43 dye loading expts indicate impaired mechanotransduction in both inner and outer cochlear hair cells   (MGI Ref ID J:109595)
  • 10 of 11 apical-coil OHCs obtained from homozygotes (aged P6-P8) exhibit absence of transduction currents with stimuli covering a wide range of bundle positions; the one transducing OHC had maximal currents of only 20 pA   (MGI Ref ID J:109595)
  • in contrast to cochlear hair cells, transduction currents obtained from vestibular (utricular) hair cells remain unaffected, consistent with a normal gait and balance behavior   (MGI Ref ID J:109595)
• absent distortion product otoacoustic emissions
  • at 2 months, homozygotes completely lack distortion product otoacoustic emissions (DPOAEs), indicating failure of OHC to amplify basilar membrane motion   (MGI Ref ID J:109595)
• cochlear inner hair cell degeneration
  • by 2 months, homozygotes exhibit significant IHC degeneration in the basal-most regions of the cochlea   (MGI Ref ID J:109595)
• cochlear outer hair cell degeneration
  • by 2 months, homozygotes exhibit significant OHC degeneration in the basal half of the cochlea   (MGI Ref ID J:109595)
  • notably, loss of OHCs is prominent in the innermost row   (MGI Ref ID J:109595)
• deafness
  • ABRs indicate that homozygotes are profoundly deaf by 3 weeks of age   (MGI Ref ID J:109595)
  • acoustic sensitivity is progressively decreased over the following month   (MGI Ref ID J:109595)
• increased or absent threshold for auditory brainstem response
  • at 3 weeks, homozygotes display elevated ABR thresholds by ~20 dB for responses to low frequency stimulation (2-2.8 kHz) and by ~60 dB for responses to higher frequency stimuli   (MGI Ref ID J:109595)
  • by 6 months, average threshold values are increased by ~10 dB for responses to higher frequency stimuli (>10 kHz), with values of 95-100 dB SPL regardless of stimulus frequency   (MGI Ref ID J:109595)
  • fewer 6-mo-old homozygotes are responseive to highest levels of stimulation (>105 dB SPL) at high frequencies (>10 kHz) relative to 3-wk-old homozygotes   (MGI Ref ID J:109595)
• organ of Corti degeneration
  • by 2 months, homozygotes exhibit significant degeneration of the organ of Corti in the basal, high frequency cochlear turn   (MGI Ref ID J:109595)
  • at 2 months, the middle and apical turns are less affected, although they do exhibit a disarray of stereociliary bundles   (MGI Ref ID J:109595)
• pillar cell degeneration
  • by 2 months, homozygotes display loss of inner and outer pillar cells in the basal-most regions of the cochlea   (MGI Ref ID J:109595)
  • loss of pillar cells results in complete collapse of the end organ in the basal cochlear turn   (MGI Ref ID J:109595)
• vision/eye phenotype
• abnormal cone electrophysiology
  • at 15 months, the amplitudes of component waves of electroretinograms are reduced by 26-37% for all stimulus conditions in light-adapted cone-only responses   (MGI Ref ID J:109595)
  • however, no gross retinal abnormalities (i.e. retinitis pigmentosa) are detected by funduscopic or histological analyses   (MGI Ref ID J:109595)
• abnormal vision
  • homozygotes exhibit age-related loss of visual function   (MGI Ref ID J:109595)
• nervous system phenotype
• abnormal cochlear hair cell stereociliary bundle morphology
  • by P2, homozygotes exhibit a disorganized cochlear hair bundle morphology, which is more prominent at P4   (MGI Ref ID J:109595)
  • no further exacerbation of hair bundle morphology occurs with increasing age, as determined at P28   (MGI Ref ID J:109595)
• • abnormal inner hair cell stereociliary bundle morphology   (MGI Ref ID J:109595)
  • abnormal outer hair cell stereociliary bundle morphology
    • at P2, many of the homozygous mutant OHC stereociliary bundles in apical coils display a less sharply defined V-shape relative to those in heterozygous OHCs   (MGI Ref ID J:109595)
    • by P4, mutant OHC stereociliary bundles display a more rounded shape and lack bilateral symmetry   (MGI Ref ID J:109595)
  • • abnormal orientation of outer hair cell stereociliary bundles
      • by P4, mutant OHC stereociliary bundles exhibit a degree of disorientation   (MGI Ref ID J:109595)
  • absent cochlear hair bundle ankle links
    • at P2, ankle links are absent from both cochlear inner and outer hair cell stereociliary bundles   (MGI Ref ID J:109595)
    • surprisingly, ankle links in mutant vestibular hair cell stereociliary bundles appear unaffected   (MGI Ref ID J:109595)
• abnormal cochlear outer hair cell physiology
  • single-cell recordings show that most cochlear OHCs fail to respond to fairly large hair bundle displacements by P7   (MGI Ref ID J:109595)
• abnormal hair cell mechanoelectric transduction
  • FM1-43 dye loading expts indicate impaired mechanotransduction in both inner and outer cochlear hair cells   (MGI Ref ID J:109595)
  • 10 of 11 apical-coil OHCs obtained from homozygotes (aged P6-P8) exhibit absence of transduction currents with stimuli covering a wide range of bundle positions; the one transducing OHC had maximal currents of only 20 pA   (MGI Ref ID J:109595)
  • in contrast to cochlear hair cells, transduction currents obtained from vestibular (utricular) hair cells remain unaffected, consistent with a normal gait and balance behavior   (MGI Ref ID J:109595)
• audiogenic seizures
  • a high intensity sound stimulus triggers audiogenic seizures that frequently continue to full tonic-clonic extension   (MGI Ref ID J:90899)
• cochlear inner hair cell degeneration
  • by 2 months, homozygotes exhibit significant IHC degeneration in the basal-most regions of the cochlea   (MGI Ref ID J:109595)
• cochlear outer hair cell degeneration
  • by 2 months, homozygotes exhibit significant OHC degeneration in the basal half of the cochlea   (MGI Ref ID J:109595)
  • notably, loss of OHCs is prominent in the innermost row   (MGI Ref ID J:109595)

View Research Applications

Research Applications

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

Mouse/Human Gene Homologs
deafness

Neurobiology Research
Hearing Defects

Research Tools
Sensorineural Research

Sensorineural Research
Eye Defects
Hearing Defects

Genes & Alleles

Gene & Allele Information provided by MGI

Allele Symbol		Gpr98tm1Pwh
Allele Name		targeted mutation 1, Perrin C White
Allele Type		Targeted (knock-out)
Common Name(s)		VLGR/delTM7; Vlgr1del7TM;
Mutation Made By		Daniel McMillan,   UT Southwestern Medical Center
Strain of Origin		129S1/Sv-Oca2<+> Tyr<+> Kitl<+>
Gene Symbol and Name		Gpr98, G protein-coupled receptor 98
Chromosome		13
Gene Common Name(s)		FEB4; MASS1; Mass1; Mgr1; Neurepin; USH2B; USH2C; VLGR1; VLGR1b; monogenic, audiogenic seizure susceptibility 1;
Molecular Note		A 691 bp segment including intron 81 and part of exon 82 was replaced with an HA tag, a 6xHis affinity purification tag, and a translation stop codon via homologous recombination. Western blot analysis confirmed expression of a single mutant protein. [MGI Ref ID J:90899]

Genotyping

Genotyping Information

Helpful Links

Genotyping resources and troubleshooting

References

References provided by MGI

Selected Reference(s)

McMillan DR; White PC. 2004. Loss of the transmembrane and cytoplasmic domains of the very large G-protein-coupled receptor-1 (VLGR1 or Mass1) causes audiogenic seizures in mice. Mol Cell Neurosci 26(2):322-9. [PubMed: 15207856]  [MGI Ref ID J:90899]

Additional References

Gpr98^tm1Pwh related

Goodyear RJ; Jones SM; Sharifi L; Forge A; Richardson GP. 2012. Hair bundle defects and loss of function in the vestibular end organs of mice lacking the receptor-like inositol lipid phosphatase PTPRQ. J Neurosci 32(8):2762-72. [PubMed: 22357859]  [MGI Ref ID J:182502]

Maerker T; van Wijk E; Overlack N; Kersten FF; McGee J; Goldmann T; Sehn E; Roepman R; Walsh EJ; Kremer H; Wolfrum U. 2008. A novel Usher protein network at the periciliary reloading point between molecular transport machineries in vertebrate photoreceptor cells. Hum Mol Genet 17(1):71-86. [PubMed: 17906286]  [MGI Ref ID J:132040]

McGee J; Goodyear RJ; McMillan DR; Stauffer EA; Holt JR; Locke KG; Birch DG; Legan PK; White PC; Walsh EJ; Richardson GP. 2006. The very large G-protein-coupled receptor VLGR1: a component of the ankle link complex required for the normal development of auditory hair bundles. J Neurosci 26(24):6543-53. [PubMed: 16775142]  [MGI Ref ID J:109595]

Health & husbandry

The genotypes of the animals provided may not reflect those discussed in the strain description or the mating scheme utilized by The Jackson Laboratory prior to cryopreservation. Please inquire for possible genotypes for this specific strain.

Health & Colony Maintenance Information

Animal Health Reports

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

Colony Maintenance

Breeding & Husbandry	When maintaining a live colony, these mice can be bred as homozygotes.

Pricing and Purchasing

Pricing, Supply Level & Notes, Controls

Control Information

	Control
	000664 C57BL/6J
Considerations for Choosing Controls
Control Pricing Information for Genetically Engineered Mutant Strains.

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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.

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