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FMR1 mutant marmosets show fragile X syndrome phenotypes
Maria Harbers1, Zefeng Wei1, Harumi Nakao1
1Laboratory of Animal Resources, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Abstract:
Fragile X syndrome (FXS) is the foremost monogenic cause of autism spectrum disorder and intellectual disability, caused by FMR1 gene silencing. Here, we report that common marmosets carrying FMR1 mutation, a non-human primate model for FXS, share common features in behavioral and molecular phenotypes with patients with FXS. Founder mutants with markedly reduced fragile X messenger ribonucleoprotein expression display hyperactivity, spontaneous seizures, and transcriptome changes in synapse-related genes that overlap with those reported in patients with FXS. Although spontaneous seizures in these mutants lead to postnatal lethality, the lethality is rescued by introducing mutations into the GRM5 gene, suggesting that elevated mGluR5 signaling contributes to the phenotype. F1 heterozygous females carrying a uniform mutation exhibit phenotypes associated with FXS, including alterations in vocal development and social preferences, electroencephalographic abnormalities, and impaired motor skills. Thus, female marmosets heterozygous for the FMR1 mutation represent a valuable translational model for investigating FXS mechanisms and potential therapeutic strategies.
Insights
Common marmosets with an FMR1 gene mutation offer a new model for Fragile X syndrome (FXS). These marmosets display FXS-like behaviors and molecular changes, aiding research into autism and intellectual disability.
Area of Science:
- Neuroscience
- Genetics
- Primate Models
Background:
- Fragile X syndrome (FXS) is a leading genetic cause of autism spectrum disorder and intellectual disability.
- FXS results from the silencing of the FMR1 gene.
Purpose of the Study:
- To establish and characterize common marmosets with an FMR1 mutation as a non-human primate model for FXS.
- To investigate the behavioral and molecular phenotypes in marmosets carrying the FMR1 mutation.
Main Methods:
- Generation of marmosets with FMR1 gene mutations.
- Assessment of behavioral phenotypes including hyperactivity, seizures, vocal development, social preferences, and motor skills.
- Analysis of molecular phenotypes, including transcriptome changes in synapse-related genes and electroencephalographic abnormalities.
Main Results:
- Founder marmosets with reduced FMR1 expression exhibited hyperactivity, spontaneous seizures, and overlapping transcriptome changes with FXS patients.
- GRM5 gene mutation rescued postnatal lethality in mutants, indicating mGluR5 signaling's role.
- F1 heterozygous females showed FXS-associated phenotypes like altered vocalizations, social behavior, EEG abnormalities, and motor deficits.
Conclusions:
- Common marmosets with FMR1 mutations serve as a valuable translational model for FXS.
- Female marmosets heterozygous for the FMR1 mutation are particularly promising for studying FXS mechanisms and therapeutic strategies.
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