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Insight and Recommendations for Fragile X-Premutation-Associated Conditions from the Fifth International Conference on FMR1 Premutation
Author(s)
Tassone, Flora
Protic, Dragana
Allen, Emily Graves
Archibald, Alison D.
Baud, Anna
Brown, Ted W.
Budimirovic, Dejan B.
Cohen, Jonathan
Dufour, Brett
Eiges, Rachel
Elvassore, Nicola
Gabis, Lidia V.
Grudzien, Samantha J.
Hall, Deborah A.
Hessl, David
Hogan, Abigail
Hunter, Jessica Ezzell
Jin, Peng
Klusek, Jessica
Kooy, R. Frank
Kraan, Claudine M.
Laterza, Cecilia
Lee, Andrea
Lipworth, Karen
Losh, Molly
Loesch, Danuta
Lozano, Reymundo
Mailick, Marsha R.
Manolopoulos, Apostolos
Martinez-Cerdeno, Veronica
McLennan, Yingratana
Miller, Robert M.
Montanaro, Federica Alice Maria
Mosconi, Matthew W.
Potter, Sarah Nelson
Raspa, Melissa
Rivera, Susan M.
Shelly, Katharine
Todd, Peter K.
Tutak, Katarzyna
Wang, Jun Yi
Wheeler, Anne
Winarni, Tri Indah
Zafarullah, Marwa
Hagerman, Randi J.
Date Issued
September 1, 2023
Type
Review
Abstract
The premutation of the fragile X messenger ribonucleoprotein 1 (FMR1) gene is characterized by an expansion of the CGG trinucleotide repeats (55 to 200 CGGs) in the 5’ untranslated region and increased levels of FMR1 mRNA. Molecular mechanisms leading to fragile X-premutation-associated conditions (FXPAC) include cotranscriptional R-loop formations, FMR1 mRNA toxicity through both RNA gelation into nuclear foci and sequestration of various CGG-repeat-binding proteins, and the repeat-associated non-AUG (RAN)-initiated translation of potentially toxic proteins. Such molecular mechanisms contribute to subsequent consequences, including mitochondrial dysfunction and neuronal death. Clinically, premutation carriers may exhibit a wide range of symptoms and phenotypes. Any of the problems associated with the premutation can appropriately be called FXPAC. Fragile X-associated tremor/ataxia syndrome (FXTAS), fragile X-associated primary ovarian insufficiency (FXPOI), and fragile X-associated neuropsychiatric disorders (FXAND) can fall under FXPAC. Understanding the molecular and clinical aspects of the premutation of the FMR1 gene is crucial for the accurate diagnosis, genetic counseling, and appropriate management of affected individuals and families. This paper summarizes all the known problems associated with the premutation and documents the presentations and discussions that occurred at the International Premutation Conference, which took place in New Zealand in 2023.
Citation
Cells, 12(18), 2023