FMR1 Iso-Seq intermediate files: FLNC and nFL reads

Over 40% of males and ~16% of female carriers of FMR1 premutation allele (55-200 CGG repeats) are at risk for developing Fragile X-associated Tremor/Ataxia Syndrome (FXTAS), an adult onset neurodegenerative disorder. On the other hand, about 20% of female carriers will develop Fragile X-associated Primary Ovarian Insufficiency (FXPOI), in addition to a number of adult-onset clinical problems (FMR1 associated disorders). Marked elevation in FMR1 mRNA levels have been observed with premutation alleles resulting in RNA toxicity. This molecular mechanism has been proposed as the leading molecular mechanism to explain the phenotypes observed in premutation carriers.

The FMR1 gene, as many housekeeping genes, undergoes alternative splicing. Using Single Molecule, Real-Time (SMRT) sequencing and qRT-PCR we have recently reported that the relative abundance of all FMR1 mRNA isoforms is significantly increased in the premutation group compared to controls. In this study, we have further investigated the transcriptional FMR1 isoforms distribution pattern in different tissues including muscle, brain, heart and testes from 3 individuals with premutation allele and FXTAS and compared them to the isoform profiles of age-matched controls. Here we report on the identification of novel isoforms, some of which are observed only in premutation carriers and might play a role in the pathogenesis of FXTAS.

Our findings suggest that the characterization of expression levels of the different FMR1 isoforms is fundamental for understanding the regulation of the FMR1 gene as well as for elucidating the mechanism(s) by which “toxic gain of function” of the FMR1 mRNA may play a role in FXTAS and/or in the other FMR1-associated conditions. In addition to the elevated levels of FMR1 isoforms, the altered abundance/ratio of the corresponding FMRP isomers may affect the overall function of FMRP in premutations.