Description

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. Mating System Heterozygote x Wild-type         (Female x Male)   19-JUN-12 Species laboratory mouse Generation N10p+N1F (13-AUG-12) Generation Definitions   Donating Investigator Zhaolan (Joe) Zhou,   University of Pennsylvania

Description
These Mecp2^T158A mice contain a missense mutation in exon 4 of the endogenous methyl-CpG binding protein 2 (Mecp2) gene. This mutation introduces the amino acid mutation T158A in the methyl CpG binding domain (MBD) of MeCP2, analogous to a MECP2 mutation found in humans with Rett Syndrome (RTT). RTT is an X-linked neurodevelopmental disorder that can be caused by mutations in the Mecp2 gene. Hemizygous males with the T158A mutation exhibit hypoactivity, poor motor control, irregular breathing, altered anxiety, and impaired learning and memory after 5-6 weeks of age. They are infertile and have a shortened lifespan, with 50% of males dying by 4 months of age. Symptoms in heterozygous females are obvious after 17 weeks of age. Heterozygous females are viable and fertile. The differences seen between the sexes is because Mecp2 is an X-linked gene. Due to X-chromosome inactivation, heterozygous females have mosaic expression of wild-type MeCP2.

Development
A targeting construct was designed to insert a loxP-flanked neomycin (neo) resistance cassette upstream of exon 4 of the methyl-CpG binding protein 2 (Mecp2) gene. This mutation introduces the amino acid mutation T158A found in humans carrying the neurodevelopmental disorder Rett Syndrome (RTT). This targeting construct was electroporated into 129Sv derived embryonic stem (ES) cells and correctly targeted ES cells were injected into C57BL/6 blastocysts. Chimeric males were bred to C57BL/6 females and offspring were bred to B6.FVB-Tg(EIIa-cre)C5379Lmgd/J transgenic mice (Stock No. 003724) to remove the neo cassette. The resulting offspring were backcrossed to C57BL/6NCrL for at least 10 generations. Upon arrival at The Jackson Laboratory, mutant mice were bred to C57BL/6NJ mice (Stock No. 005304) for at least one generation to establish the colony.

Control Information

	Control
	Wild-type from the colony
	005304 C57BL/6NJ	(approximate)
Considerations for Choosing Controls

Related Strains

Strains carrying other alleles of Mecp2

003890	B6.129P2(C)-Mecp2tm1.1Bird/J
007177	B6.129P2-Mecp2tm1Bird/J
006849	B6.129P2-Mecp2tm2Bird/J
005439	B6.129S-Mecp2tm1Hzo/J
018282	B6.Cg-Mapttm1(Mecp2)Jae/LimmJ
006847	B6;129P2-Mecp2tm1Bird/J
016207	B6N.129-Mecp2tm1.1Vnar/J
012602	STOCK Mecp2tm1.1Irsf/J
014610	STOCK Mecp2tm3.1Bird/J

View Strains carrying other alleles of Mecp2     (9 strains)

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).

Rett Syndrome; RTT

- Potential model based on gene homology relationships. Phenotypic similarity to the human disease has not been tested. Angelman Syndrome; AS   (MECP2) Autism, Susceptibility to, X-Linked 3; AUTSX3   (MECP2) Encephalopathy, Neonatal Severe, Due to Mecp2 Mutations   (MECP2) Lubs X-Linked Mental Retardation Syndrome; MRXSL   (MECP2) Mental Retardation, X-Linked, Syndromic 13; MRXS13   (MECP2)

View Mammalian Phenotype Terms

Mammalian Phenotype Terms provided by MGI

      assigned by genotype

Mecp2^tm1.1Joez/Mecp2⁺

        B6.129-Mecp2^tm1.1Joez

• mortality/aging
• *normal* mortality/aging
  • mice exhibit normal survival   (MGI Ref ID J:181311)
• behavior/neurological phenotype
• abnormal behavior
  • mice exhibit RTT-like symptoms after 17 weeks of age   (MGI Ref ID J:181311)
• • hypoactivity
    • at 20, but not 12, weeks of age   (MGI Ref ID J:181311)
• growth/size phenotype
• increased body weight   (MGI Ref ID J:181311)

Mecp2^tm1.1Joez/Y

        B6.129-Mecp2^tm1.1Joez

• mortality/aging
• premature death
  • 50% of mice die by 16 weeks of age   (MGI Ref ID J:181311)
• behavior/neurological phenotype
• abnormal behavior
  • mice exhibit RTT-like symptoms after 5 weeks of age   (MGI Ref ID J:181311)
• • abnormal gait
    • with splaying hind limbs upon movement   (MGI Ref ID J:181311)
  • abnormal motor learning
    • impaired motor learning on a rotarod   (MGI Ref ID J:181311)
  • akinesia   (MGI Ref ID J:181311)
  • decreased anxiety-related response
    • in an elevated zero maze   (MGI Ref ID J:181311)
  • hypoactivity
    • at 11, but not 3, weeks of age   (MGI Ref ID J:181311)
    • not as severe as in Mecp2^tm1.1Jae hemizygotes   (MGI Ref ID J:181311)
  • impaired contextual conditioning behavior   (MGI Ref ID J:181311)
  • impaired coordination
    • on a rotarod   (MGI Ref ID J:181311)
    • not as severe as in Mecp2^tm1.1Jae hemizygotes   (MGI Ref ID J:181311)
  • impaired cued conditioning behavior   (MGI Ref ID J:181311)
  • limb grasping
    • at 13 weeks of age   (MGI Ref ID J:181311)
  • seizures
    • occasionally after 5 weeks of age   (MGI Ref ID J:181311)
• nervous system phenotype
• abnormal brain wave pattern
  • at P30, mice exhibit reduction in event-related power in delta, sigma and alpha low-frequencies compared with wild-type mice   (MGI Ref ID J:181311)
  • at P30, mice exhibit less of an increase in phase-locking factor at delta and high gamma frequencies compared with wild-type mice   (MGI Ref ID J:181311)
  • at P90, awake mice exhibit increased high-gamma frequency oscillation power compared with wild-type mice   (MGI Ref ID J:181311)
  • at P90, mice exhibit an increase in latency of P1, N1 and P2 peaks and reduction in the amplitudes of the N1 and P2 peaks of event-related potential compared with wild-type mice   (MGI Ref ID J:181311)
  • at P90, mice exhibit attenuated event-related power in both low- and high-frequency oscillation compared with wild-type mice   (MGI Ref ID J:181311)
  • at P90, mice exhibit less of an increase in phase-locking factor at all frequencies compared with wild-type mice   (MGI Ref ID J:181311)
  • however, mice exhibit normal power and event-related potential at P30   (MGI Ref ID J:181311)
• decreased brain weight
  • at P30 and P90   (MGI Ref ID J:181311)
• seizures
  • occasionally after 5 weeks of age   (MGI Ref ID J:181311)
• growth/size phenotype
• decreased body weight
  • between 4 and 8 weeks of age   (MGI Ref ID J:181311)

View Research Applications

Research Applications

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

Mouse/Human Gene Homologs
Rett syndrome

Neurobiology Research
Behavioral and Learning Defects
      high anxiety
Neurodevelopmental Defects
      Rett's syndrome

Reproductive Biology Research
Fertility Defects
      males only

Genes & Alleles

Gene & Allele Information provided by MGI

Allele Symbol		Mecp2tm1.1Joez
Allele Name		targeted mutation 1.1, Zhaolan Zhou
Allele Type		Targeted (knock-in)
Common Name(s)		MeCP2 T158A; Mecp2T158A;
Mutation Made By		Zhaolan (Joe) Zhou,   University of Pennsylvania
Strain of Origin		129
Promoter		Mecp2, methyl CpG binding protein 2, mouse, laboratory
Molecular Note		A targeting construct was designed to insert a loxP-flanked neomycin (neo) resistance cassette upstream of exon 4. A point mutation was introduced in exon 4, resulting in the amino acid mutation, T158A, found in humans carrying the neurodevelopmental disorder Rett Syndrome (RTT). An additional point mutation was introduced at codon 160 to produce a silent mutation that allowed for identification of targeted ES cells. Cre-mediated recombination removed the neo cassette. [MGI Ref ID J:181311]

Genotyping

Genotyping Information

Genotyping Protocols

Generic Cre Melt Curve Analysis, Melt Curve Analysis
Mecp2^tm1.1Joez, End Point Analysis

Helpful Links

Genotyping resources and troubleshooting

References

References provided by MGI

Selected Reference(s)

Goffin D; Allen M; Zhang L; Amorim M; Wang IT; Reyes AR; Mercado-Berton A; Ong C; Cohen S; Hu L; Blendy JA; Carlson GC; Siegel SJ; Greenberg ME; Zhou Z. 2012. Rett syndrome mutation MeCP2 T158A disrupts DNA binding, protein stability and ERP responses. Nat Neurosci 15(2):274-83. [PubMed: 22119903]  [MGI Ref ID J:181311]

Health & husbandry

Health & Colony Maintenance Information

Animal Health Reports

Room Number           AX18

Colony Maintenance

Breeding & Husbandry	When maintaining a live colony, heterozygous females may be bred to wildtype males. Hemizygous males are infertile and have a shortened lifespan, with 50% of males dying by 4 months of age.
Mating System	Heterozygote x Wild-type         (Female x Male)   19-JUN-12
Diet Information	LabDiet® 5K20

Pricing and Purchasing

Pricing, Supply Level & Notes, Controls

Control Information

	Control
	Wild-type from the colony
	005304 C57BL/6NJ	(approximate)
Considerations for Choosing Controls
Control Pricing Information for Genetically Engineered Mutant Strains.

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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.

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