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| These mice possess a M712T mutation in the Gne gene. Additionally, the exon harboring the mutation (exon 12) is floxed. These mice may have applications in studies related to neuromuscular disorder hereditary inclusion body myopathy (HIBM). | |||||||||||||||||||||||||||
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Description
Strain Information
Type Coisogenic; Mutant Strain; Targeted Mutation; Additional information on Genetically Engineered and Mutant Mice. Visit our online Nomenclature tutorial. Species laboratory mouse Donating Investigator Daniel Darvish, ARM (Advancement of Research for Myopath Description
These mice express the M712T mutant form of the glucosamine (Gne) gene. Exon 12 of the Gne gene is flanked by loxP sites allowing for Cre-recombinase inducible tissue-specific deletion. Glucosamine catalyzes the first 2 committed, rate-limiting steps in the biosynthesis of sialic acid and can be inactivated via feedback inhibition caused by cytosolic CMP-sialic acid levels. Mutations in this gene have been associated with the development of hereditary inclusion body myopathy (HIBM) which is an adult onset, neuromuscular disorder characterized by slow progressive muscle weakness and atrophy. The M712T mutation is commonly found in people with HIBM in Iranian-Jewish families. In these HIBM cases, the muscle fibers degenerate and develop filamentous nuclear inclusions and cytoplasmic rimmed vacuoles. Homozygous mice with this mutation do not live past P3 and have no visible milk spot. They are smaller than littermates, weighing as little as 70% the weight of controls. They exhibit subcutaneous hemorrhaging and cystic tubular dilation in the kidneys. They also have excess red blood cells in the glomeruli, Bowman space, collecting ducts, renal tubules, and urinary space. They also exhibit glomerular proteinuria and defects in podocyte morphology. The postnatal lethalily phenotype can be rescued by prenatal administration of sialic acid or its precursor N-acetylglucosamine. Heterozygous mice display a more moderate phenotype, with less red blood cell infiltration in the kidney. These mice do not exhibit a skeletal muscle phenotype which may be due to mice and humans utilizing different forms of sialic acid.Development
A targeting construct was designed to insert a loxP site upstream of exon 12 and a frt-flanked neomycin (neo) resistance cassette, followed by a second loxP site downstream of exon 12 of the glucosamine (Gne) gene. Point mutations were introduced in exon 12 resulting in the M712T mutation commonly found in Iranian-Jewish families with hereditary inclusion body myopathy (HIBM). This targeting construct was electroporated into C57BL/6J embryonic stem (ES) cells and correctly targeted ES cells were injected into blastocysts. The resulting chimeric males were bred with C57BL/6J females, and the resulting offspring were backcrossed to C57BL/6J mice. Upon arrival at The Jackson Laboratory, mutant mice were bred to C57BL/6J mice (Stock No. 000664)for at least one generation to establish the colony.
Control Information
| Control | ||
|---|---|---|
| Wild-type from the colony | ||
| 000664 C57BL/6J | (approximate) | |
| Considerations for Choosing Controls | ||
Phenotype
Phenotype Information
View Related Disease (OMIM) Terms
Related Disease (OMIM) Terms provided by MGI
- Potential model based on gene homology relationships. Phenotypic similarity to the human disease has not been tested. Inclusion Body Myopathy 2, Autosomal Recessive; IBM2 (GNE)
Nonaka Myopathy; NM (GNE)
Sialuria (GNE)
assigned by genotype
Gnetm1Mhzg/Gnetm1Mhzg
involves: C57BL/6J
- mortality/aging
- complete postnatal lethality
- homozygotes die between P1 and P3 days after birth, with only one male mouse surviving beyond weaning (P21); however, normal ratios are observed at E17-E19, indicating no embryonic lethality (MGI Ref ID J:122172)
- when mice are fed 5 mg N-acetylmannosamine (ManNAc) per ml water during matings, 12 homozygous pups survive beyond P3; 9/12 die between P6 and P12, with continued ManNAc treatment (until P21) (MGI Ref ID J:122172)
- the survivors remain smaller than littermates (MGI Ref ID J:122172)
- growth/size phenotype
- decreased body weight
- renal/urinary system phenotype
- abnormal renal glomerular capsule morphology
- abnormal podocyte morphology
- at P2, homozygotes exhibit podocytopathy likely due to hyposialylation of specific membrane glycoproteins (MGI Ref ID J:122172)
- abnormal podocyte slit junction morphology
- fused podocyte foot processes
- at P2, podocyte foot processes are largely fused (MGI Ref ID J:122172)
- podocyte foot process effacement
- abnormal renal glomerulus basement membrane morphology
- abnormal renal tubule morphology
- red blood cell infiltrates are observed in proximal and distal convoluted tubules and collecting ducts (MGI Ref ID J:122172)
- cortical renal glomerulopathies
- single surviving male homozygote euthanized at 8.5 months showed kidney changes consistent with glomerulopathies (MGI Ref ID J:122172)
- hydronephrosis
- single surviving male homozygote euthanized at 8.5 months showed severe bilateral hydronephrosis (MGI Ref ID J:122172)
- increased urine protein level
- kidney hemorrhage
- cardiovascular system phenotype
- kidney hemorrhage
- homeostasis/metabolism phenotype
- increased blood urea nitrogen level
- increased urine protein level
- muscle phenotype
- *normal* muscle phenotype
- behavior/neurological phenotype
- absent gastric milk in neonates
- at P2, a prominent milkspot is sometimes absent (MGI Ref ID J:122172)
This mouse can be used to support research in many areas including:
Cell Biology Research
Vesicular Trafficking
Internal/Organ Research
Kidney Defects
Neurobiology Research
Ataxia (Movement) Defects
Cre-lox System
loxP-flanked Sequences
Research Tools
Cre-lox System
loxP-flanked Sequences
Genes & Alleles
Gene & Allele Information provided by MGI
| Allele Symbol | Gnetm1Mhzg | ||
|---|---|---|---|
| Allele Name | targeted mutation 1, Marjan Huizing | ||
| Allele Type | Targeted (knock-in) | ||
| Common Name(s) | GneM712T; | ||
| Mutation Made By | Marjan Huizing, National Institutes of Health | ||
| Strain of Origin | C57BL/6J | ||
| Promoter | Gne, glucosamine (UDP-N-acetyl)-2-epimerase/N-acetylmannosamine kinase, mouse, laboratory | ||
| Molecular Note | A targeting vector was designed to insert the M712T substitution in exon 12. LoxP sites were inserted upstream of exon 12 and downstream of an frt-flanked PGK-neo in intron 12. [MGI Ref ID J:122172] | ||
References
References provided by MGI
Selected Reference(s)
Galeano B; Klootwijk R; Manoli I; Sun M; Ciccone C; Darvish D; Starost MF; Zerfas PM; Hoffmann VJ; Hoogstraten-Miller S; Krasnewich DM; Gahl WA; Huizing M. 2007. Mutation in the key enzyme of sialic acid biosynthesis causes severe glomerular proteinuria and is rescued by N-acetylmannosamine. J Clin Invest 117(6):1585-94. [PubMed: 17549255] [MGI Ref ID J:122172]
Additional References
Gnetm1Mhzg relatedKakani S; Yardeni T; Poling J; Ciccone C; Niethamer T; Klootwijk ED; Manoli I; Darvish D; Hoogstraten-Miller S; Zerfas P; Tian E; Ten Hagen KG; Kopp JB; Gahl WA; Huizing M. 2012. The Gne M712T Mouse as a Model for Human Glomerulopathy. Am J Pathol 180(4):1431-40. [PubMed: 22322304] [MGI Ref ID J:181998]
Niethamer TK; Yardeni T; Leoyklang P; Ciccone C; Astiz-Martinez A; Jacobs K; Dorward HM; Zerfas PM; Gahl WA; Huizing M. 2012. Oral monosaccharide therapies to reverse renal and muscle hyposialylation in a mouse model of GNE myopathy. Mol Genet Metab 107(4):748-55. [PubMed: 23122659] [MGI Ref ID J:190982]
Paccalet T; Coulombe Z; Tremblay JP. 2010. Ganglioside GM3 levels are altered in a mouse model of HIBM: GM3 as a cellular marker of the disease. PLoS One 5(4):e10055. [PubMed: 20383336] [MGI Ref ID J:160169]
Health & husbandry
Health & Colony Maintenance Information
Colony Maintenance
Breeding & Husbandry When maintaining a live colony, mice may be bred a heterozygotes. The donating investigator reports that homozygous mice do not live past P3. This lethal phenotype can be rescued by administrating sialic acid or its precursor, N-acetylglucosamine, to the dam.
Pricing and Purchasing
Pricing, Supply Level & Notes, Controls
This strain is currently Awaiting Transfer from the Donor.
This strain was accepted into the JAX® Repository on 08-FEB-12.
View All Strains Awaiting Transfer from the Donor, In Progress and On Hold
Control Information
| Control | ||
|---|---|---|
| Wild-type from the colony | ||
| 000664 C57BL/6J | (approximate) | |
| Considerations for Choosing Controls | ||
| Control Pricing Information for Genetically Engineered Mutant Strains. | ||
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