Human Molecular Genetics Advance Access originally published online on April 18, 2009
Human Molecular Genetics 2009 18(13):2443-2451; doi:10.1093/hmg/ddp182
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Ectopic expression of CGG containing mRNA is neurotoxic in mammals
1 Department of Molecular and Human Genetics 2 Interdepartmental Program in Cell and Molecular Biology 3 Developmental Neurogenetics Laboratory, Department of Neurology, Baylor College of Medicine, 904E MS BCM0225, One Baylor Plaza, Houston, TX 77030, USA 4 CBG Department of Clinical Genetics, Erasmus MC, PO Box 2040 3000, CA, Rotterdam, The Netherlands
* To whom correspondence should be addressed. Tel: +1 7137984787; Fax: +1 7137981116; Email: nelson{at}bcm.edu
Received February 12, 2009; Accepted April 14, 2009
Fragile X-associated Tremor/Ataxia Syndrome (FXTAS) is a progressive neurodegenerative disorder that has been diagnosed in a substantial fraction of older male fragile X premutation carriers. Patients affected by FXTAS have elevated levels of ribo-rCGG repeat containing FMR1 mRNA with normal to slightly reduced levels of FMRP in blood leukocytes. Coupled with the absence of FXTAS in fragile X syndrome patients, this suggests premutation-sized elongated rCGG repeats in the FMR1 transcript rather than alterations in the levels of FMRP are responsible for the FXTAS pathology. Mice expressing rCGG in the context of Fmr1 or the enhanced green fluorescent protein specifically in Purkinje neurons were generated to segregate the effects of rCGG from alterations in Fmr1 and to provide evidence that rCGG is necessary and sufficient to cause pathology similar to human FXTAS. The models exhibit the presence of intranuclear inclusions in Purkinje neurons, Purkinje neuron cell death and behavioral deficits. These results demonstrate that rCGG expressed in Purkinje neurons outside the context of Fmr1 mRNA can result in neuronal pathology in a mammalian system and demonstrate that expanded CGG repeats in RNA are the likely cause of the neurodegeneration in FXTAS.