The premutation of the fragile X messenger ribonucleoprotein 1 (FMR1) gene is characterized by an expansion of CGG trinucleotide repeats (from 55 to 200 CGGs) in the 5′ untranslated region and by elevated FMR1 mRNA levels. The molecular mechanisms leading to fragile X premutation–associated conditions (FXPAC) include the formation of co-transcriptional R-loops, FMR1 mRNA toxicity through RNA gelation into nuclear foci and the sequestration of various CGG repeat–binding proteins, as well as repeat-associated non-AUG (RAN) translation of potentially toxic proteins. These molecular mechanisms contribute to downstream consequences such as mitochondrial dysfunction and neuronal death.
Clinically, carriers of the premutation may exhibit a wide spectrum of symptoms and phenotypes. Any issue associated with the premutation can appropriately be referred to as FXPAC. The fragile X–associated tremor/ataxia syndrome (FXTAS), fragile X–associated primary ovarian insufficiency (FXPOI), and fragile X–associated neuropsychiatric disorders (FXAND) all fall under the FXPAC umbrella.
Understanding the molecular and clinical aspects of the FMR1 premutation is crucial for accurate diagnosis, genetic counseling, and appropriate management of affected individuals and families. This article summarizes all known issues related to the premutation and documents the presentations and discussions held at the International Premutation Conference, which took place in New Zealand in 2023.
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