Cells (Sep 2023)
Insight and Recommendations for Fragile X-Premutation-Associated Conditions from the Fifth International Conference on <i>FMR1</i> Premutation
- 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
Affiliations
- Flora Tassone
- Department of Biochemistry and Molecular Medicine, School of Medicine, University of California Davis, Sacramento, CA 95817, USA
- Dragana Protic
- Department of Pharmacology, Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Belgrade, 11129 Belgrade, Serbia
- Emily Graves Allen
- Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA
- Alison D. Archibald
- Victorian Clinical Genetics Services, Royal Children’s Hospital, Melbourne, VIC 3052, Australia
- Anna Baud
- Department of Gene Expression, Institute of Molecular Biology and Biotechnology, Adam Mickiewicz University, Uniwersytetu Poznańskiego 6, 61-614 Poznan, Poland
- Ted W. Brown
- Central Clinical School, University of Sydney, Sydney, NSW 2006, Australia
- Dejan B. Budimirovic
- Department of Psychiatry, Fragile X Clinic, Kennedy Krieger Institute, Baltimore, MD 21205, USA
- Jonathan Cohen
- Fragile X Alliance Clinic, Melbourne, VIC 3161, Australia
- Brett Dufour
- MIND Institute, University of California Davis, Davis, CA 95817, USA
- Rachel Eiges
- Stem Cell Research Laboratory, Medical Genetics Institute, Shaare Zedek Medical Center Affiliated with the Hebrew University School of Medicine, Jerusalem 91031, Israel
- Nicola Elvassore
- Veneto Institute of Molecular Medicine (VIMM), 35129 Padova, Italy
- Lidia V. Gabis
- Keshet Autism Center Maccabi Wolfson, Holon 5822012, Israel
- Samantha J. Grudzien
- Department of Neurology, University of Michigan, 4148 BSRB, 109 Zina Pitcher Place, Ann Arbor, MI 48109, USA
- Deborah A. Hall
- Department of Neurological Sciences, Rush University, Chicago, IL 60612, USA
- David Hessl
- MIND Institute, University of California Davis, Davis, CA 95817, USA
- Abigail Hogan
- Department of Communication Sciences and Disorders, Arnold School of Public Health, University of South Carolina, Columbia, SC 29208, USA
- Jessica Ezzell Hunter
- RTI International, Research Triangle Park, NC 27709, USA
- Peng Jin
- Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA
- Poonnada Jiraanont
- Faculty of Medicine, King Mongkut’s Institute of Technology Ladkrabang, Bangkok 10520, Thailand
- Jessica Klusek
- Department of Communication Sciences and Disorders, Arnold School of Public Health, University of South Carolina, Columbia, SC 29208, USA
- R. Frank Kooy
- Department of Medical Genetics, University of Antwerp, 2000 Antwerp, Belgium
- Claudine M. Kraan
- Department of Paediatrics, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, VIC 3052, Australia
- Cecilia Laterza
- Veneto Institute of Molecular Medicine (VIMM), 35129 Padova, Italy
- Andrea Lee
- Fragile X New Zealand, Nelson 7040, New Zealand
- Karen Lipworth
- Fragile X Association of Australia, Brookvale, NSW 2100, Australia
- Molly Losh
- Roxelyn and Richard Pepper Department of Communication Sciences and Disorders, Northwestern University, Evanston, IL 60201, USA
- Danuta Loesch
- School of Psychology and Public Health, La Trobe University, Melbourne, VIC 3086, Australia
- Reymundo Lozano
- Departments of Genetics and Genomic Sciences and Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Marsha R. Mailick
- Waisman Center, University of Wisconsin-Madison, Madison, WI 53705, USA
- Apostolos Manolopoulos
- Intramural Research Program, Laboratory of Clinical Investigation, National Institute on Aging, Baltimore, MD 21224, USA
- Veronica Martinez-Cerdeno
- MIND Institute, University of California Davis, Davis, CA 95817, USA
- Yingratana McLennan
- Department 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
- Robert M. Miller
- National Fragile X Foundation, Washington, DC 20005, USA
- Federica Alice Maria Montanaro
- Child and Adolescent Neuropsychiatry Unit, Department of Neuroscience, Bambino Gesù Children’s Hospital, IRCCS, 00165 Rome, Italy
- Matthew W. Mosconi
- Schiefelbusch Institute for Life Span Studies, University of Kansas, Lawrence, KS 66045, USA
- Sarah Nelson Potter
- RTI International, Research Triangle Park, NC 27709, USA
- Melissa Raspa
- RTI International, Research Triangle Park, NC 27709, USA
- Susan M. Rivera
- Department of Psychology, University of Maryland, College Park, MD 20742, USA
- Katharine Shelly
- Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA
- Peter K. Todd
- Department of Neurology, University of Michigan, 4148 BSRB, 109 Zina Pitcher Place, Ann Arbor, MI 48109, USA
- Katarzyna Tutak
- Department of Gene Expression, Institute of Molecular Biology and Biotechnology, Adam Mickiewicz University, Uniwersytetu Poznańskiego 6, 61-614 Poznan, Poland
- Jun Yi Wang
- Center for Mind and Brain, University of California Davis, Davis, CA 95618, USA
- Anne Wheeler
- RTI International, Research Triangle Park, NC 27709, USA
- Tri Indah Winarni
- Center for Biomedical Research (CEBIOR), Faculty of Medicine, Universitas Diponegoro, Semarang 502754, Central Java, Indonesia
- Marwa Zafarullah
- Department of Biochemistry and Molecular Medicine, School of Medicine, University of California Davis, Sacramento, CA 95817, USA
- Randi J. Hagerman
- MIND Institute, University of California Davis, Davis, CA 95817, USA
- DOI
- https://doi.org/10.3390/cells12182330
- Journal volume & issue
-
Vol. 12,
no. 18
p. 2330
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.
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