Overview

Also Known As:Fmr1 CGG KI

This Fmr1 CGG repeat expansion premutation knock-in (Fmr1 CGG KI) mouse model is useful for studying Fragile X Tremor/Ataxia Syndrome (FXTAS).

Donating Investigator

David L Nelson, Baylor College of Medicine

Rob Willemsen, Erasmus Medical Center

Genetic overview

Genetic Background	Generation

Fmr1^tm2Cgr

Allele Type	Gene Symbol	Gene Name
Targeted (Humanized sequence)	Fmr1	fragile X mental retardation 1

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Research Applications

Neurobiology Research

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Base Price

Starting at:

$2,854.50 Domestic price Cryo Recovery

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Details

Detailed Description

The human fragile X mental retardation 1 (FMR1) gene on the X chromosome contains an unstable CGG repeat in its 5' untranslated region. While repeat length in the normal population is polymorphic (5–54 CGG repeats), CGG repeat expansions greater than 200 (i.e., the full mutation) have hypermethylation that results in FMR1 gene silencing and fragile X syndrome. Individuals with CGG repeat expansions of 55–200 (premutation CGG or preCGG) can develop the progressive neurodegenerative disease fragile X-associated tremor/ataxia syndrome (FXTAS).

The Fmr1 CGG repeat expansion premutation knock-in allele (Fmr1 CGG KI) was generated by substituting the endogenous mouse (CGG)₈ with a human (CGG)₉₈. Similar to humans, germline passage of this allele in mice can result in contraction and/or expansion of the meiotically unstable CGG repeat element; resulting in a broad range of allele sizes (<70 to >300 CGG repeats).

The Jackson Laboratory will attempt to have Fmr1 CGG KI mice with >90 CGG repeats [(CGG)₉₀₊] available.

In general, Fmr1 CGG KI mice show elevated Fmr1 mRNA levels, defects in neuronal morphology and migration, and ubiquitin-positive neuronal inclusions throughout the brain. Fmr1 CGG KI mice exhibit aberrant behavior, including mild learning deficits and increased anxiety. The donating investigator reports that homozygous females and hemizygous males are viable and fertile, and when bred together they observe no breeding abnormalities (litter size/frequency, nursing, etc.). The phenotype of mice with specific repeat lengths are described below.

Hemizygous males with (CGG)_102-110 exhibit ubiquitin positive intranuclear neuronal inclusions.

Hemizygous males with (CGG)_106-123 exhibit abnormal learning/memory/conditioning (52 weeks old), impaired coordination (52 weeks old and 72 weeks old), decreased grip strength (52 weeks old) and abnormal behavior (72 weeks old). However, gait, activity levels and exploration levels are normal at 72 weeks of age.

Homozygous females and hemizygous males with up to (CGG)₂₀₀ are viable and fertile.

In Fmr1 CGG KI mice, the CGG repeat number is subject to germline and somatic instability, and may expand or contract. When using mouse models with unstable CGG repeat length, it is strongly recommended the CGG repeat number be quantified in all the experimental animals; all animals in all experimental groups should carry comparable CGG repeat sizes.

Development

The Fmr1 CGG repeat expansion premutation knock-in allele (Fmr1 CGG KI) was created by Dr. Ben A. Oostra (Erasmus University). The targeting vector was designed to replace the endogenous 8 CGG repeat sequence [(CGG)₈] in the promoter of the fragile X mental retardation syndrome 1 gene (Fmr1) on the X chromosome with a human 98 CGG repeat sequence [(CGG)₉₈] and also place a loxP-flanked neo cassette into intron 1. The construct was electroporated into 129P2/OlaHsd-derived E14 embryonic stem (ES) cells. Correctly targeted ES cells were injected into recipient blastocysts, and chimeras were bred with FVB and/or C57BL/6 to establish the colony.
At some point, the (CGG)₉₈/neo animals were bred with germline Cre recombinase-expressing mice (undisclosed genetic background background) to delete the neo cassette. The resulting mice are called (CGG)₉₈/neo- (or Fmr1 CGG KI).

In ~2007, Fmr1 CGG KI mice on a C57BL/6J;FVB/N genetic background with black coat color were sent to Dr. David L. Nelson (Baylor College of Medicine). There, Dr. Nelson backcrossed the colony one generation to C57BL/6J females.
Fmr1 CGG KI males with a donor-reported ~130 CGG repeats [(CGG)_~130] and black coat color were sent to The Jackson Laboratory Repository in 2016. Upon arrival, sperm was cryopreserved. To establish our live colony, an aliquot of frozen sperm was used to fertilize C57BL/6J oocytes (Stock No. 000664).

Selected References

Bontekoe CJ; Bakker CE; Nieuwenhuizen IM; van der Linde H; Lans H; de Lange D; Hirst MC; Oostra BA. 2001. Instability of a (CGG)98 repeat in the Fmr1 promoter. Hum Mol Genet 10(16):1693-9PubMed: 11487573 MGI: J:71202

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Genetics

Fmr1^tm2Cgr

Allele Symbol: Fmr1^tm2Cgr

Allele Name	targeted mutation 2, Ben Oostra
Allele Type	Targeted (Humanized sequence)
Allele Synonym(s)	CGG(98)
Gene Symbol and Name	Fmr1, fragile X mental retardation 1
Gene Synonym(s)
Strain of Origin	129P2/OlaHsd
Chromosome	X
Molecular Note	The mouse promoter 8 CGG repeat sequence was replaced with a human 98 CGG repeat and a floxed neo cassette via homologous recombination. The targeted allele was verified by PCR analysis. Germline passage of this allele results in contraction and expansion of the CGG repeats.

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).

fragile X-associated tremor/ataxia syndrome

Research Areas By Phenotype

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

Neurobiology Research
- Ataxia (Movement) Defects
- Neurodegeneration
- Behavioral and Learning Defects
  - high anxiety
- Fragile X Mental Retardation Syndrome

Mammalian Phenotype Terms by Genotype

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

Genotype: Fmr1^tm2Cgr/Y
involves: 129P2/OlaHsd

nervous system phenotype

neuronal intranuclear inclusions
- male mice with 102 to 110 CGG repeats exhibit ubiquitin positive intranuclear neuronal inclusions

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

Genotype: Fmr1^tm2Cgr/Y
involves: 129P2/OlaHsd * C57BL/6J * FVB

behavior/neurological phenotype

abnormal behavior
- at 72 weeks, male mice (106 to 123 CGG repeats) in an open field test travel shorter distances and enter the center circle fewer times than wild-type mice
- Normal - however, activity and exploration levels are normal

abnormal learning/memory/conditioning
- at 52 weeks, male mice (106 to 123 CGG repeats) in a Morris water maze exhibit impaired visual-spatial learning and memory compared to wild-type mice with increased escape latency and path length

decreased grip strength
- at 52 weeks, male mice (106 to 123 CGG repeats) exhibit decreased latency to first fall in a wire suspension test and fall more often than wild-type mice
- Normal - however, performance in a wire suspension test is normal at 20 and 72 weeks of age

impaired coordination
- at 52 and 72 weeks, male mice (106 to 123 CGG repeats) exhibit reduced latency to fall on a rotarod test compared to at 20 weeks of age
- at 72 weeks, male mice (106 to 123 CGG repeats) exhibit a lower number of segments crossed on a stationary beam compared to wild-type mice
- Normal - however, mice perform as wild-type mice in a gait test
- male mice (106 to 123 CGG repeats) exhibit decreased performance on a rotarod as they age unlike wild-type mice

References

Bontekoe CJ; Bakker CE; Nieuwenhuizen IM; van der Linde H; Lans H; de Lange D; Hirst MC; Oostra BA. 2001. Instability of a (CGG)98 repeat in the Fmr1 promoter. Hum Mol Genet 10(16):1693-9PubMed: 11487573 MGI: J:71202

Additional - Fmr1^tm2Cgr related

Technical Support

CONTACT TECHNICAL SUPPORT

Genotyping Protocols
- Standard PCR:Fmr1 Alternate2 (presence/absence)
- Genotyping resources and troubleshooting
Breeding Considerations

The Fmr1 locus is on the X chromosome. When maintaining a live colony, wildtype females from the colony may be bred with hemizygous males. Alternatively, heterozygous females may be bred with wildtype males from the colony. The donating investigator reports that homozygous females and hemizygous males are viable and fertile, and when bred together they observe no breeding abnormalities (litter size/frequency, nursing, etc.).
- Additional Breeding and Husbandry Support
Mating System
- Homozygote x Hemizygote
Citation
When using the Fmr1 CGG KI mouse strain in a publication, please cite the originating article(s) and include JAX stock #024102 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
	Females heterozygous for Fmr1<tm2Cgr>, male will be wildtype.

Related Products and Services

Frozen Mouse Embryo	STOCK Fmr1<tm2Cgr>/DlnJ Frozen Embryo	$2595.00
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Frozen Mouse Embryo	STOCK Fmr1<tm2Cgr>/DlnJ Frozen Embryo	$3373.50
Frozen Mouse Embryo	STOCK Fmr1<tm2Cgr>/DlnJ Frozen Embryo	$3373.50

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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.

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Also Known As:Fmr1 CGG KI

Donating Investigator

Genetic overview

Research Applications

Base Price

Detailed Description

Development

Selected References

Fmr1tm2Cgr

Allele Symbol: Fmr1tm2Cgr

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).

Research Areas By Phenotype

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

Mammalian Phenotype Terms by Genotype

Genotype: Fmr1tm2Cgr/Yinvolves: 129P2/OlaHsd

nervous system phenotype

Genotype: Fmr1tm2Cgr/Yinvolves: 129P2/OlaHsd * C57BL/6J * FVB

behavior/neurological phenotype

References

Additional - Fmr1tm2Cgr related

Genotyping Protocols

Breeding Considerations

Mating System

Citation

Animal Health Reports

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

Live Mouse

Cryorecovery - Pricing

Related Products and Services

Payment Terms and Conditions

The Jackson Laboratory's Genotype Promise

Terms Of Use

Additional Use Restrictions Apply

Licensing Information

JAX® Mice, Products & Services Conditions of Use

No Warranty

Credit for PRODUCTS or SERVICES

Animal Care and Use for SERVICES

No Liability

Fmr1^tm2Cgr

Allele Symbol: Fmr1^tm2Cgr

Genotype: Fmr1^tm2Cgr/Y
involves: 129P2/OlaHsd

Genotype: Fmr1^tm2Cgr/Y
involves: 129P2/OlaHsd * C57BL/6J * FVB

Additional - Fmr1^tm2Cgr related