FMR1 mRNA from full mutation alleles is associated with ABC-CFX scores in males with fragile X syndrome

Emma K. Baker; Marta Arpone; Claudine Kraan; Minh Bui; Carolyn Rogers; Michael Field; Lesley Bretherton; Ling Ling; Alexandra Ure; Jonathan Cohen; Matthew F. Hunter; Lorena Santa María; Victor Faundes; Bianca Curotto; Paulina Morales; Cesar Trigo; Isabel Salas; Angelica Alliende; David J. Amor; David E. Godler

doi:10.1038/s41598-020-68465-6

FMR1 mRNA from full mutation alleles is associated with ABC-C_FX scores in males with fragile X syndrome

Emma K. Baker, Marta Arpone, Claudine Kraan, Minh Bui, Carolyn Rogers, Michael Field, Lesley Bretherton, Ling Ling, Alexandra Ure, Jonathan Cohen, Matthew F. Hunter, Lorena Santa María, Victor Faundes, Bianca Curotto, Paulina Morales, Cesar Trigo, Isabel Salas, Angelica Alliende, David J. Amor, David E. Godler^*

^*Corresponding author for this work

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Abstract

Fragile X syndrome (FXS) is caused by a hypermethylated full mutation (FM) expansion with ≥ 200 CGG repeats, and a decrease in FMR1 mRNA and its protein. However, incomplete silencing from FM alleles has been associated with more severe autism features in FXS males. This study compared scores on the Aberrant Behavior Checklist-Community-FXS version (ABC-C_FX) in 62 males affected with FXS (3 to 32 years) stratified based on presence or absence of mosaicism and/or FMR1 mRNA silencing. Associations between ABC-C_FX subscales and FMR1 mRNA levels, assessed using real-time PCR relative standard curve method, were also examined. The FXS group mosaic for premutation (PM: 55–199 CGGs) and FM alleles had lower irritability (p = 0.014) and inappropriate speech (p < 0.001) scores compared to males with only FM alleles and complete loss of FMR1 mRNA. The PM/FM mosaic group also showed lower inappropriate speech scores compared to the incomplete silencing (p = 0.002) group. Increased FMR1 mRNA levels were associated with greater irritability (p < 0.001), and lower health-related quality of life scores (p = 0.004), but only in the incomplete silencing FM-only group. The findings suggest that stratification based on CGG sizing and FMR1 mRNA levels may be warranted in future research and clinical trials utilising ABC-C_FX subscales as outcome measures.

Original language	English
Article number	11701
Pages (from-to)	1-8
Number of pages	8
Journal	Scientific Reports
Volume	10
Issue number	1
Early online date	16 Jul 2020
DOIs	https://doi.org/10.1038/s41598-020-68465-6
Publication status	Published - 1 Dec 2020
Externally published	Yes

Bibliographical note

Copyright the Author(s) 2020. 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.

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Publisher version (open access)Final published version, 1.1 MBLicence: CC BY

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Baker, E. K., Arpone, M., Kraan, C., Bui, M., Rogers, C., Field, M., Bretherton, L., Ling, L., Ure, A., Cohen, J., Hunter, M. F., Santa María, L., Faundes, V., Curotto, B., Morales, P., Trigo, C., Salas, I., Alliende, A., Amor, D. J., & Godler, D. E. (2020). FMR1 mRNA from full mutation alleles is associated with ABC-C_FX scores in males with fragile X syndrome. Scientific Reports, 10(1), 1-8. Article 11701. https://doi.org/10.1038/s41598-020-68465-6

@article{d951bff29dab4b8daa495708636d8534,

title = "FMR1 mRNA from full mutation alleles is associated with ABC-CFX scores in males with fragile X syndrome",

abstract = "Fragile X syndrome (FXS) is caused by a hypermethylated full mutation (FM) expansion with ≥ 200 CGG repeats, and a decrease in FMR1 mRNA and its protein. However, incomplete silencing from FM alleles has been associated with more severe autism features in FXS males. This study compared scores on the Aberrant Behavior Checklist-Community-FXS version (ABC-CFX) in 62 males affected with FXS (3 to 32 years) stratified based on presence or absence of mosaicism and/or FMR1 mRNA silencing. Associations between ABC-CFX subscales and FMR1 mRNA levels, assessed using real-time PCR relative standard curve method, were also examined. The FXS group mosaic for premutation (PM: 55–199 CGGs) and FM alleles had lower irritability (p = 0.014) and inappropriate speech (p < 0.001) scores compared to males with only FM alleles and complete loss of FMR1 mRNA. The PM/FM mosaic group also showed lower inappropriate speech scores compared to the incomplete silencing (p = 0.002) group. Increased FMR1 mRNA levels were associated with greater irritability (p < 0.001), and lower health-related quality of life scores (p = 0.004), but only in the incomplete silencing FM-only group. The findings suggest that stratification based on CGG sizing and FMR1 mRNA levels may be warranted in future research and clinical trials utilising ABC-CFX subscales as outcome measures.",

author = "Baker, \{Emma K.\} and Marta Arpone and Claudine Kraan and Minh Bui and Carolyn Rogers and Michael Field and Lesley Bretherton and Ling Ling and Alexandra Ure and Jonathan Cohen and Hunter, \{Matthew F.\} and \{Santa Mar{\'i}a\}, Lorena and Victor Faundes and Bianca Curotto and Paulina Morales and Cesar Trigo and Isabel Salas and Angelica Alliende and Amor, \{David J.\} and Godler, \{David E.\}",

note = "Copyright the Author(s) 2020. 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 = "2020",

month = dec,

day = "1",

doi = "10.1038/s41598-020-68465-6",

language = "English",

volume = "10",

pages = "1--8",

journal = "Scientific Reports",

issn = "2045-2322",

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Baker, EK, Arpone, M, Kraan, C, Bui, M, Rogers, C, Field, M, Bretherton, L, Ling, L, Ure, A, Cohen, J, Hunter, MF, Santa María, L, Faundes, V, Curotto, B, Morales, P, Trigo, C, Salas, I, Alliende, A, Amor, DJ & Godler, DE 2020, 'FMR1 mRNA from full mutation alleles is associated with ABC-C_FX scores in males with fragile X syndrome', Scientific Reports, vol. 10, no. 1, 11701, pp. 1-8. https://doi.org/10.1038/s41598-020-68465-6

TY - JOUR

T1 - FMR1 mRNA from full mutation alleles is associated with ABC-CFX scores in males with fragile X syndrome

AU - Baker, Emma K.

AU - Arpone, Marta

AU - Kraan, Claudine

AU - Bui, Minh

AU - Rogers, Carolyn

AU - Field, Michael

AU - Bretherton, Lesley

AU - Ling, Ling

AU - Ure, Alexandra

AU - Cohen, Jonathan

AU - Hunter, Matthew F.

AU - Santa María, Lorena

AU - Faundes, Victor

AU - Curotto, Bianca

AU - Morales, Paulina

AU - Trigo, Cesar

AU - Salas, Isabel

AU - Alliende, Angelica

AU - Amor, David J.

AU - Godler, David E.

N1 - Copyright the Author(s) 2020. 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 - 2020/12/1

Y1 - 2020/12/1

N2 - Fragile X syndrome (FXS) is caused by a hypermethylated full mutation (FM) expansion with ≥ 200 CGG repeats, and a decrease in FMR1 mRNA and its protein. However, incomplete silencing from FM alleles has been associated with more severe autism features in FXS males. This study compared scores on the Aberrant Behavior Checklist-Community-FXS version (ABC-CFX) in 62 males affected with FXS (3 to 32 years) stratified based on presence or absence of mosaicism and/or FMR1 mRNA silencing. Associations between ABC-CFX subscales and FMR1 mRNA levels, assessed using real-time PCR relative standard curve method, were also examined. The FXS group mosaic for premutation (PM: 55–199 CGGs) and FM alleles had lower irritability (p = 0.014) and inappropriate speech (p < 0.001) scores compared to males with only FM alleles and complete loss of FMR1 mRNA. The PM/FM mosaic group also showed lower inappropriate speech scores compared to the incomplete silencing (p = 0.002) group. Increased FMR1 mRNA levels were associated with greater irritability (p < 0.001), and lower health-related quality of life scores (p = 0.004), but only in the incomplete silencing FM-only group. The findings suggest that stratification based on CGG sizing and FMR1 mRNA levels may be warranted in future research and clinical trials utilising ABC-CFX subscales as outcome measures.

AB - Fragile X syndrome (FXS) is caused by a hypermethylated full mutation (FM) expansion with ≥ 200 CGG repeats, and a decrease in FMR1 mRNA and its protein. However, incomplete silencing from FM alleles has been associated with more severe autism features in FXS males. This study compared scores on the Aberrant Behavior Checklist-Community-FXS version (ABC-CFX) in 62 males affected with FXS (3 to 32 years) stratified based on presence or absence of mosaicism and/or FMR1 mRNA silencing. Associations between ABC-CFX subscales and FMR1 mRNA levels, assessed using real-time PCR relative standard curve method, were also examined. The FXS group mosaic for premutation (PM: 55–199 CGGs) and FM alleles had lower irritability (p = 0.014) and inappropriate speech (p < 0.001) scores compared to males with only FM alleles and complete loss of FMR1 mRNA. The PM/FM mosaic group also showed lower inappropriate speech scores compared to the incomplete silencing (p = 0.002) group. Increased FMR1 mRNA levels were associated with greater irritability (p < 0.001), and lower health-related quality of life scores (p = 0.004), but only in the incomplete silencing FM-only group. The findings suggest that stratification based on CGG sizing and FMR1 mRNA levels may be warranted in future research and clinical trials utilising ABC-CFX subscales as outcome measures.

UR - https://www.scopus.com/pages/publications/85088100872

U2 - 10.1038/s41598-020-68465-6

DO - 10.1038/s41598-020-68465-6

M3 - Article

C2 - 32678152

AN - SCOPUS:85088100872

SN - 2045-2322

VL - 10

SP - 1

EP - 8

JO - Scientific Reports

JF - Scientific Reports

IS - 1

M1 - 11701

ER -

FMR1 mRNA from full mutation alleles is associated with ABC-C_FX scores in males with fragile X syndrome

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