Journal Article

Insight and Recommendations for Fragile X-Premutation-Associated Conditions from the Fifth International Conference on FMR1 Premutation

Laterza, Cecilia, Winarni, Tri Indah, Loesch, Danuta, McLennan, Yingratana, Budimirovic, Dejan B., Dufour, Brett, Tassone, Flora, Tutak, Katarzyna, Lipworth, Karen, Baud, Anna, Shelly, Katharine, Kooy, R. Frank, Elvassore, Nicola, Grudzien, Samantha J., Lozano, Reymundo, Manolopoulos, Apostolos, Hogan, Abigail, Mailick, Marsha R., Montanaro, Federica Alice Maria, Lee, Andrea, Hall, Deborah A., Losh, Molly, Archibald, Alison D., Kraan, Claudine M., Potter, Sarah Nelson, Zafarullah, Marwa, Klusek, Jessica, Miller, Robert M., Mosconi, Matthew W., Todd, Peter K., Allen, Emily Graves, Hunter, Jessica Ezzell, Raspa, Melissa, Wang, Jun Yi, Brown, Ted W., Martinez-Cerdeno, Veronica, Hagerman, Randi J., Gabis, Lidia V., Hessl, David, Cohen, Jonathan, Eiges, Rachel, Wheeler, Anne, Rivera, Susan M., Protic, Dragana, Jiraanont, Poonnada, Jin, Peng

2023

Overview

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.

• Publisher: MDPI AG,MDPI
• Subject: 5' Untranslated Regions / Anxiety / Ataxia / Attention deficit hyperactivity disorder / Autism / Clinical aspects / Females / FMR1 gene / FMR1 molecular and clinical / FMR1 premutation / FMR1 protein / Fragile X Mental Retardation Protein - genetics / Fragile X Mental Retardation Protein - metabolism / Fragile X syndrome / Fragile X Syndrome - diagnosis / Fragile X Syndrome - genetics / Fragile X Syndrome - therapy / FXAND / FXPAC / FXPOI / FXTAS / Genetic counseling / Genotype & phenotype / Humans / Hypertension / Intellectual disabilities / Magnetic resonance imaging / Males / Menopause / Mental disorders / Mental health / Molecular modelling / mRNA / Mutation - genetics / Phenotypes / Review / RNA, Messenger - metabolism / Toxicity / Tremor / Trinucleotide Repeat Expansion - genetics / Trinucleotide repeats / Womens health