Insight and recommendations for fragile X-premutation-associated conditions from the Fifth International Conference on FMR1 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

doi:10.3390/cells12182330

Insight and recommendations for fragile X-premutation-associated conditions from the Fifth International Conference on FMR1 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 KlusekR. 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^*

^*Corresponding author for this work

Research output: Contribution to journal › Review article › peer-review

51 Citations (Scopus)

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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.

Original language	English
Article number	2330
Pages (from-to)	1-69
Number of pages	69
Journal	Cells
Volume	12
Issue number	18
DOIs	https://doi.org/10.3390/cells12182330
Publication status	Published - 21 Sept 2023
Externally published	Yes

Bibliographical note

Copyright the Author(s) 2023. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

Keywords

FMR1 molecular and clinical
FMR1 premutation
FXAND
FXPAC
FXPOI
FXTAS

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10.3390/cells12182330Licence: CC BY

Publisher version (open access)Final published version, 4.5 MBLicence: CC BY

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Tassone, F., Protic, D., Allen, E. G., Archibald, A. D., Baud, A., Brown, T. W., Budimirovic, D. B., Cohen, J., Dufour, B., Eiges, R., Elvassore, N., Gabis, L. V., Grudzien, S. J., Hall, D. A., Hessl, D., Hogan, A., Hunter, J. E., Jin, P., Jiraanont, P., ... Hagerman, R. J. (2023). Insight and recommendations for fragile X-premutation-associated conditions from the Fifth International Conference on FMR1 Premutation. Cells, 12(18), 1-69. Article 2330. https://doi.org/10.3390/cells12182330

@article{2481255ba0064c2992049071099bb228,

title = "Insight and recommendations for fragile X-premutation-associated conditions from the Fifth International Conference on FMR1 Premutation",

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{\textquoteright} 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 molecular and clinical, FMR1 premutation, FXAND, FXPAC, FXPOI, FXTAS",

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

note = "Copyright the Author(s) 2023. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.",

year = "2023",

month = sep,

day = "21",

doi = "10.3390/cells12182330",

language = "English",

volume = "12",

pages = "1--69",

journal = "Cells",

issn = "2073-4409",

publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",

number = "18",

}

Tassone, F, Protic, D, Allen, EG, Archibald, AD, Baud, A, Brown, TW, Budimirovic, DB, Cohen, J, Dufour, B, Eiges, R, Elvassore, N, Gabis, LV, Grudzien, SJ, Hall, DA, Hessl, D, Hogan, A, Hunter, JE, Jin, P, Jiraanont, P, Klusek, J, Kooy, RF, Kraan, CM, Laterza, C, Lee, A, Lipworth, K, Losh, M, Loesch, D, Lozano, R, Mailick, MR, Manolopoulos, A, Martinez-Cerdeno, V, McLennan, Y, Miller, RM, Montanaro, FAM, Mosconi, MW, Potter, SN, Raspa, M, Rivera, SM, Shelly, K, Todd, PK, Tutak, K, Wang, JY, Wheeler, A, Winarni, TI, Zafarullah, M & Hagerman, RJ 2023, 'Insight and recommendations for fragile X-premutation-associated conditions from the Fifth International Conference on FMR1 Premutation', Cells, vol. 12, no. 18, 2330, pp. 1-69. https://doi.org/10.3390/cells12182330

TY - JOUR

T1 - Insight and recommendations for fragile X-premutation-associated conditions from the Fifth International Conference on FMR1 Premutation

AU - Tassone, Flora

AU - Protic, Dragana

AU - Allen, Emily Graves

AU - Archibald, Alison D.

AU - Baud, Anna

AU - Brown, Ted W.

AU - Budimirovic, Dejan B.

AU - Cohen, Jonathan

AU - Dufour, Brett

AU - Eiges, Rachel

AU - Elvassore, Nicola

AU - Gabis, Lidia V.

AU - Grudzien, Samantha J.

AU - Hall, Deborah A.

AU - Hessl, David

AU - Hogan, Abigail

AU - Hunter, Jessica Ezzell

AU - Jin, Peng

AU - Jiraanont, Poonnada

AU - Klusek, Jessica

AU - Kooy, R. Frank

AU - Kraan, Claudine M.

AU - Laterza, Cecilia

AU - Lee, Andrea

AU - Lipworth, Karen

AU - Losh, Molly

AU - Loesch, Danuta

AU - Lozano, Reymundo

AU - Mailick, Marsha R.

AU - Manolopoulos, Apostolos

AU - Martinez-Cerdeno, Veronica

AU - McLennan, Yingratana

AU - Miller, Robert M.

AU - Montanaro, Federica Alice Maria

AU - Mosconi, Matthew W.

AU - Potter, Sarah Nelson

AU - Raspa, Melissa

AU - Rivera, Susan M.

AU - Shelly, Katharine

AU - Todd, Peter K.

AU - Tutak, Katarzyna

AU - Wang, Jun Yi

AU - Wheeler, Anne

AU - Winarni, Tri Indah

AU - Zafarullah, Marwa

AU - Hagerman, Randi J.

N1 - Copyright the Author(s) 2023. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

PY - 2023/9/21

Y1 - 2023/9/21

N2 - 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.

AB - 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.

KW - FMR1 molecular and clinical

KW - FMR1 premutation

KW - FXAND

KW - FXPAC

KW - FXPOI

KW - FXTAS

UR - https://www.scopus.com/pages/publications/85172759046

U2 - 10.3390/cells12182330

DO - 10.3390/cells12182330

M3 - Review article

C2 - 37759552

SN - 2073-4409

VL - 12

SP - 1

EP - 69

JO - Cells

JF - Cells

IS - 18

M1 - 2330

ER -

Insight and recommendations for fragile X-premutation-associated conditions from the Fifth International Conference on FMR1 Premutation

Abstract

Bibliographical note

Keywords

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