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 (&lt;70 to &gt;300 CGG repeats). The Jackson Laboratory will attempt to have Fmr1 CGG KI mice with &gt;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.

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

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