Table 1.

Summary of the models that have been invoked as mechanisms for FXTAS pathogenesis

Mechanism class	Initiating species	Mechanism	Role in human disease	Citations
Protein sequestration by the CGG-repeat RNA				131,134,135
	hnRNP A2/B1	Both hnRNP A2/B1 and Purα appear to bind preferentially, at least in vitro, to shorter (~20 CGG) repeat RNAs, which renders them less likely candidates for FXTAS pathogenesis	Have mediating effects on Drosophila models of CGG-repeat–induced neurodegeneration. Notwithstanding their role(s) in mitigating the phenotypes in animal models, roles for Purα and hnRNP A2/B1 have yet to be demonstrated in human disease or in murine models of FXTAS.	136–138
	Purα	(see above) Transcriptional activator also thought to be involved in the control of DNA replication	(see above)	136–139
	Sam68	Altered mRNA splicing an RNA-binding protein that belongs to the “signal transduction and activation of RNA” (STAR) family	For Sam68, there is clear evidence of insufficiency in animals and humans; with altered splicing noted in FXTAS patients. However, a critical test of these candidate proteins will be whether they have any direct primary or secondary role in FXTAS pathogenesis in humans.	63,65
	DGCR8	With Drosha, reduced processing of microRNA precursors DGCR8, part of the microprocessor complex that processes micro (mi)RNA precursors in the nucleus		136, 140–143
FMRP insufficiency	FMRP			21,71–74
Antisense FMR1 RNAs	RNAs			144–147
RAN translation	polyGly-containing peptides			78,148
R-loop/DNA damage response	R-loops, gH2AX			83,84