Fmr1 Iso-Seq: Per Sample Intermediate Files

<em>FMR1</em> premutation carriers (55-200 CGG repeats) are at risk for developing Fragile X-associated Tremor/Ataxia Syndrome (FXTAS), an adult onset neurodegenerative disorder. In addition, 20 % of female carriers will develop Fragile X-associated Primary Ovarian Insufficiency (FXPOI), in addition to a number of clinical problems affecting premutation carriers throughout their life span. Marked elevation in <em>FMR1</em> mRNA levels have been observed with premutation alleles resulting in RNA toxicity, the leading molecular mechanism proposed for the <em>FMR1</em> associated disorders observed in premutation carriers. The <em>FMR1</em> gene, undergoes alternative splicing and we have recently reported that the relative abundance of all <em>FMR1</em> mRNA isoforms is significantly increased in premutation carriers. In this study, we further investigated the transcriptional <em>FMR1</em> isoforms distribution pattern in different tissues and identified a total of 49 isoforms, some of which observed only in premutation carriers and which might play a role in the pathogenesis of FXTAS. Further, we investigated the distribution pattern and expression levels of the <em>FMR1</em> isoforms in asymptomatic premutation carriers and in those with FXTAS and found no significant difference between the two groups. Our findings suggest that the characterization of the expression levels of the different <em>FMR1</em> isoforms is fundamental for understanding the regulation of the <em>FMR1</em> gene as imbalance in their expression could lead to an altered functional diversity with neurotoxic consequences. Their characterization will also help to elucidating the mechanism(s) by which “toxic gain of function” of the <em>FMR1</em> mRNA may play a role in FXTAS and/or in the other <em>FMR1</em>-associated conditions.