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

Sci Rep. 2020 Jul 16;10(1):11701. doi: 10.1038/s41598-020-68465-6.

Authors

Emma K Baker^{1

2

3}, Marta Arpone^{1

2

4}, Claudine Kraan^{1

2}, Minh Bui⁵, Carolyn Rogers⁶, Michael Field⁶, Lesley Bretherton¹, Ling Ling¹, Alexandra Ure^{2

7

8

9}, Jonathan Cohen^{10

11}, Matthew F Hunter¹², Lorena Santa María¹³, Victor Faundes¹³, Bianca Curotto¹³, Paulina Morales¹³, Cesar Trigo¹³, Isabel Salas¹³, Angelica Alliende¹³, David J Amor^#^{2

7}, David E Godler^#^{14

15}

Affiliations

¹ Diagnosis and Development, Murdoch Children's Research Institute, Royal Children's Hospital, 50 Flemington Road, Parkville, VIC, 3052, Australia.
² Department of Paediatrics, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, VIC, Australia.
³ School of Psychology and Public Health, La Trobe University, Bundoora, VIC, Australia.
⁴ Brain and Mind, Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, VIC, Australia.
⁵ Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Carlton, VIC, Australia.
⁶ Genetics of Learning Disability Service, Hunter Genetics, Hunter New England Health, Waratah, NSW, Australia.
⁷ Neurodisability and Rehabilitation, Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, VIC, Australia.
⁸ Royal Children's Hospital, Melbourne, VIC, Australia.
⁹ Department of Pediatrics, Monash University, Clayton, VIC, Australia.
¹⁰ Fragile X Alliance Inc, North Caulfield, VIC, Australia.
¹¹ Centre for Developmental Disability Health Victoria, Monash University, Clayton, VIC, Australia.
¹² Monash Genetics, Monash Health, Clayton, VIC, Australia.
¹³ Laboratory of Molecular Cytogenetics, Department of Genetics and Metabolic Diseases, Institute of Nutrition and Food Technology (INTA), University of Chile, Santiago, Chile.
¹⁴ Diagnosis and Development, Murdoch Children's Research Institute, Royal Children's Hospital, 50 Flemington Road, Parkville, VIC, 3052, Australia. david.godler@mcri.edu.au.
¹⁵ Department of Paediatrics, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, VIC, Australia. david.godler@mcri.edu.au.

^# Contributed equally.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Adult
Alleles*
Australia / epidemiology
Child
Child, Preschool
Chile / epidemiology
Cohort Studies
DNA Methylation
Fragile X Mental Retardation Protein / genetics*
Fragile X Syndrome / epidemiology
Fragile X Syndrome / genetics*
Gene Silencing
Humans
Male
Mosaicism*
Quality of Life
RNA, Messenger / genetics*
Real-Time Polymerase Chain Reaction
Research Design*
Trinucleotide Repeat Expansion / genetics
Young Adult

Substances

FMR1 protein, human
RNA, Messenger
Fragile X Mental Retardation Protein