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

Author:

Tassone Flora12ORCID,Protic Dragana34ORCID,Allen Emily Graves5,Archibald Alison D.678ORCID,Baud Anna9,Brown Ted W.101112,Budimirovic Dejan B.1314ORCID,Cohen Jonathan15ORCID,Dufour Brett216,Eiges Rachel17,Elvassore Nicola1819,Gabis Lidia V.2021ORCID,Grudzien Samantha J.222324,Hall Deborah A.25,Hessl David226ORCID,Hogan Abigail27,Hunter Jessica Ezzell28,Jin Peng5ORCID,Jiraanont Poonnada29,Klusek Jessica27ORCID,Kooy R. Frank30ORCID,Kraan Claudine M.731ORCID,Laterza Cecilia1819ORCID,Lee Andrea32,Lipworth Karen11,Losh Molly33,Loesch Danuta34ORCID,Lozano Reymundo35ORCID,Mailick Marsha R.36,Manolopoulos Apostolos37ORCID,Martinez-Cerdeno Veronica216,McLennan Yingratana16,Miller Robert M.38,Montanaro Federica Alice Maria3940ORCID,Mosconi Matthew W.414243,Potter Sarah Nelson28ORCID,Raspa Melissa28ORCID,Rivera Susan M.44,Shelly Katharine5,Todd Peter K.2245ORCID,Tutak Katarzyna9ORCID,Wang Jun Yi46,Wheeler Anne28,Winarni Tri Indah47,Zafarullah Marwa1ORCID,Hagerman Randi J.248ORCID

Affiliation:

1. Department of Biochemistry and Molecular Medicine, School of Medicine, University of California Davis, Sacramento, CA 95817, USA

2. MIND Institute, University of California Davis, Davis, CA 95817, USA

3. Department of Pharmacology, Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Belgrade, 11129 Belgrade, Serbia

4. Fragile X Clinic, Special Hospital for Cerebral Palsy and Developmental Neurology, 11040 Belgrade, Serbia

5. Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA

6. Victorian Clinical Genetics Services, Royal Children’s Hospital, Melbourne, VIC 3052, Australia

7. Department of Paediatrics, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, VIC 3052, Australia

8. Genomics in Society Group, Murdoch Children’s Research Institute, Royal Children’s Hospital, Melbourne, VIC 3052, Australia

9. Department of Gene Expression, Institute of Molecular Biology and Biotechnology, Adam Mickiewicz University, Uniwersytetu Poznańskiego 6, 61-614 Poznan, Poland

10. Central Clinical School, University of Sydney, Sydney, NSW 2006, Australia

11. Fragile X Association of Australia, Brookvale, NSW 2100, Australia

12. NYS Institute for Basic Research in Developmental Disabilities, New York, NY 10314, USA

13. Department of Psychiatry, Fragile X Clinic, Kennedy Krieger Institute, Baltimore, MD 21205, USA

14. Department of Psychiatry & Behavioral Sciences-Child Psychiatry, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA

15. Fragile X Alliance Clinic, Melbourne, VIC 3161, Australia

16. 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

17. Stem Cell Research Laboratory, Medical Genetics Institute, Shaare Zedek Medical Center Affiliated with the Hebrew University School of Medicine, Jerusalem 91031, Israel

18. Veneto Institute of Molecular Medicine (VIMM), 35129 Padova, Italy

19. Department of Industrial Engineering, University of Padova, 35131 Padova, Italy

20. Keshet Autism Center Maccabi Wolfson, Holon 5822012, Israel

21. Faculty of Medicine, Tel-Aviv University, Tel Aviv 6997801, Israel

22. Department of Neurology, University of Michigan, 4148 BSRB, 109 Zina Pitcher Place, Ann Arbor, MI 48109, USA

23. Neuroscience Graduate Program, University of Michigan, Ann Arbor, MI 48109, USA

24. Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA

25. Department of Neurological Sciences, Rush University, Chicago, IL 60612, USA

26. Department of Psychiatry and Behavioral Sciences, School of Medicine, University of California Davis, Sacramento, CA 95817, USA

27. Department of Communication Sciences and Disorders, Arnold School of Public Health, University of South Carolina, Columbia, SC 29208, USA

28. RTI International, Research Triangle Park, NC 27709, USA

29. Faculty of Medicine, King Mongkut’s Institute of Technology Ladkrabang, Bangkok 10520, Thailand

30. Department of Medical Genetics, University of Antwerp, 2000 Antwerp, Belgium

31. Diagnosis and Development, Murdoch Children’s Research Institute, Melbourne, VIC 3052, Australia

32. Fragile X New Zealand, Nelson 7040, New Zealand

33. Roxelyn and Richard Pepper Department of Communication Sciences and Disorders, Northwestern University, Evanston, IL 60201, USA

34. School of Psychology and Public Health, La Trobe University, Melbourne, VIC 3086, Australia

35. Departments of Genetics and Genomic Sciences and Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA

36. Waisman Center, University of Wisconsin-Madison, Madison, WI 53705, USA

37. Intramural Research Program, Laboratory of Clinical Investigation, National Institute on Aging, Baltimore, MD 21224, USA

38. National Fragile X Foundation, Washington, DC 20005, USA

39. Child and Adolescent Neuropsychiatry Unit, Department of Neuroscience, Bambino Gesù Children’s Hospital, IRCCS, 00165 Rome, Italy

40. Department of Education, Psychology, Communication, University of Bari Aldo Moro, 70121 Bari, Italy

41. Schiefelbusch Institute for Life Span Studies, University of Kansas, Lawrence, KS 66045, USA

42. Clinical Child Psychology Program, University of Kansas, Lawrence, KS 66045, USA

43. Kansas Center for Autism Research and Training (K-CART), University of Kansas, Lawrence, KS 66045, USA

44. Department of Psychology, University of Maryland, College Park, MD 20742, USA

45. Ann Arbor Veterans Administration Healthcare, Ann Arbor, MI 48105, USA

46. Center for Mind and Brain, University of California Davis, Davis, CA 95618, USA

47. Center for Biomedical Research (CEBIOR), Faculty of Medicine, Universitas Diponegoro, Semarang 502754, Central Java, Indonesia

48. Department of Pediatrics, School of Medicine, University of California Davis, Sacramento, CA 95817, USA

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.

Funder

NIH

Publisher

MDPI AG

Subject

General Medicine

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