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. Keywords: FMR1 premutation, FXPAC, FXTAS, FXAND, FXPOI, FMR1 molecular and clinical
SHOW FULL ABSTRACT CITATION BIBTEX RIS
Flora Tassone, Dragana Protic, Emily Graves Allen et al.. Insight and Recommendations for Fragile X-Premutation-Associated Conditions from the Fifth International Conference on FMR1 Premutation. Cells. (2023). https://doi.org/10.3390/cells12182330 Flora Tassone, Dragana Protic, Emily Graves Allen, Alison D Archibald, Anna Baud, Ted W Brown, Dejan B Budimirovic, Jonathan Cohen, Brett Dufour, Rachel Eiges, Nicola Elvassore, Lidia V Gabis, Samantha J Grudzien, Deborah A Hall, David Hessl, Abigail Hogan, Jessica Ezzell Hunter, Peng Jin, Poonnada Jiraanont, Jessica Klusek, R Frank Kooy, Claudine M Kraan, Cecilia Laterza, Andrea Lee, Karen Lipworth, Molly Losh, Danuta Loesch, Reymundo Lozano, Marsha R Mailick, Apostolos Manolopoulos, Veronica Martinez-Cerdeno, Yingratana McLennan, Robert M Miller, Federica Alice Maria Montanaro, Matthew W Mosconi, Sarah Nelson Potter, Melissa Raspa, Susan M Rivera, Katharine Shelly, Peter K Todd, Katarzyna Tutak, Jun Yi Wang, Anne Wheeler, Tri Indah Winarni, Marwa Zafarullah, Randi J Hagerman
1Department of Biochemistry and Molecular Medicine, School of Medicine, University of California Davis, Sacramento, CA 95817, USA; [email protected] 2MIND Institute, University of California Davis, Davis, CA 95817, USA; [email protected] (B.D.); [email protected] (D.H.); [email protected] (V.M.-C.) 3Department of Pharmacology, Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Belgrade, 11129 Belgrade, Serbia; [email protected] 4Fragile X Clinic, Special Hospital for Cerebral Palsy and Developmental Neurology, 11040 Belgrade, Serbia 5Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA; [email protected] (E.G.A.); [email protected] (P.J.); [email protected] (K.S.) 6Victorian Clinical Genetics Services, Royal Children’s Hospital, Melbourne, VIC 3052, Australia; [email protected] 7Department of Paediatrics, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, VIC 3052, Australia; [email protected] 8Genomics in Society Group, Murdoch Children’s Research Institute, Royal Children’s Hospital, Melbourne, VIC 3052, Australia 9Department of Gene Expression, Institute of Molecular Biology and Biotechnology, Adam Mickiewicz University, Uniwersytetu Poznańskiego 6, 61-614 Poznan, Poland; [email protected] (A.B.); [email protected] (K.T.) 10Central Clinical School, University of Sydney, Sydney, NSW 2006, Australia; [email protected] 11Fragile X Association of Australia, Brookvale, NSW 2100, Australia; [email protected] 12NYS Institute for Basic Research in Developmental Disabilities, New York, NY 10314, USA 13Department of Psychiatry, Fragile X Clinic, Kennedy Krieger Institute, Baltimore, MD 21205, USA; [email protected] 14Department of Psychiatry & Behavioral Sciences-Child Psychiatry, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA 15Fragile X Alliance Clinic, Melbourne, VIC 3161, Australia; [email protected] 16Department of Pathology and Laboratory Medicine, Institute for Pediatric Regenerative Medicine, Shriners Hospitals for Children of Northern California, School of Medicine, University of California Davis, Sacramento, CA 95817, USA; [email protected] 17Stem Cell Research Laboratory, Medical Genetics Institute, Shaare Zedek Medical Center Affiliated with the Hebrew University School of Medicine, Jerusalem 91031, Israel; [email protected] 18Veneto Institute of Molecular Medicine (VIMM), 35129 Padova, Italy; [email protected] (N.E.); [email protected] (C.L.) 19Department of Industrial Engineering, University of Padova, 35131 Padova, Italy 20Keshet Autism Center Maccabi Wolfson, Holon 5822012, Israel; [email protected] 21Faculty of Medicine, Tel-Aviv University, Tel Aviv 6997801, Israel 22Department of Neurology, University of Michigan, 4148 BSRB, 109 Zina Pitcher Place, Ann Arbor, MI 48109, USA; [email protected] (S.J.G.); [email protected] (P.K.T.) 23Neuroscience Graduate Program, University of Michigan, Ann Arbor, MI 48109, USA 24Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA 25Department of Neurological Sciences, Rush University, Chicago, IL 60612, USA; [email protected] 26Department of Psychiatry and Behavioral Sciences, School of Medicine, University of California Davis, Sacramento, CA 95817, USA 27Department of Communication Sciences and Disorders, Arnold School of Public Health, University of South Carolina, Columbia, SC 29208, USA; [email protected] (A.H.); [email protected] (J.K.) 28RTI International, Research Triangle Park, NC 27709, USA; [email protected] (J.E.H.); [email protected] (S.N.P.); [email protected] (M.R.); [email protected] (A.W.) 29Faculty of Medicine, King Mongkut’s Institute of Technology Ladkrabang, Bangkok 10520, Thailand; [email protected] 30Department of Medical Genetics, University of Antwerp, 2000 Antwerp, Belgium; [email protected] 31Diagnosis and Development, Murdoch Children’s Research Institute, Melbourne, VIC 3052, Australia 32Fragile X New Zealand, Nelson 7040, New Zealand; [email protected] 33Roxelyn and Richard Pepper Department of Communication Sciences and Disorders, Northwestern University, Evanston, IL 60201, USA; [email protected] 34School of Psychology and Public Health, La Trobe University, Melbourne, VIC 3086, Australia; [email protected] 35Departments of Genetics and Genomic Sciences and Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; [email protected] 36Waisman Center, University of Wisconsin-Madison, Madison, WI 53705, USA; [email protected] 37Intramural Research Program, Laboratory of Clinical Investigation, National Institute on Aging, Baltimore, MD 21224, USA; [email protected] 38National Fragile X Foundation, Washington, DC 20005, USA; [email protected] 39Child and Adolescent Neuropsychiatry Unit, Department of Neuroscience, Bambino Gesù Children’s Hospital, IRCCS, 00165 Rome, Italy; [email protected] 40Department of Education, Psychology, Communication, University of Bari Aldo Moro, 70121 Bari, Italy 41Schiefelbusch Institute for Life Span Studies, University of Kansas, Lawrence, KS 66045, USA; [email protected] 42Clinical Child Psychology Program, University of Kansas, Lawrence, KS 66045, USA 43Kansas Center for Autism Research and Training (K-CART), University of Kansas, Lawrence, KS 66045, USA 44Department of Psychology, University of Maryland, College Park, MD 20742, USA; [email protected] 45Ann Arbor Veterans Administration Healthcare, Ann Arbor, MI 48105, USA 46Center for Mind and Brain, University of California Davis, Davis, CA 95618, USA; [email protected] 47Center for Biomedical Research (CEBIOR), Faculty of Medicine, Universitas Diponegoro, Semarang 502754, Central Java, Indonesia; [email protected] 48Department of Pediatrics, School of Medicine, University of California Davis, Sacramento, CA 95817, USA 