Open Access BASE2020

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

Baker, Emma K; Arpone, Marta; Kraan, Claudine; Bui, Minh; Rogers, Carolyn; Field, Michael; Bretherton, Lesley; Ling, Ling; Ure, Alexandra; Cohen, Jonathan; Hunter, Matthew F; Santa María Vásquez, Lorena; Faúndes Gómez, Víctor; Curotto, Bianca; Morales, Paulina; Trigo, César; Salas, Isabel; Alliende Rodríguez, Angélica; Amor, David J; Godler, David E

Open Access

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. ; Victorian Government's Operational Infrastructure Support Program National Health and Medical Research Council of Australia 1049299 1103389 Murdoch Children's Research Institute Royal Children's Hospital Foundation Next Generation Clinical Researchers Program - Career Development Fellowship - Medical Research Future Fund MRF1141334 Financial Markets Foundation for Children (Australia) 2017 - 361 Genetics of Learning Disability (GOLD) Service Australian Government International Postgraduate Research Scholarships (IPRS) Australian Government University of Melbourne Diagnosis and Development group of the Murdoch Children's Research Institute

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