Incomplete silencing of full mutation alleles in males with fragile X syndrome is associated with autistic features

Molecular Autism

Lesley Bretherton¹  Minh Bui²  David J. Amor³  Emma K. Baker⁴  Solange M. Aliaga⁴  Howard R. Slater⁴  Claudine M. Kraan⁴  Marta Arpone⁴  Ling Ling⁴  David E. Godler⁴  Jonathan Cohen⁵  Carolyn Rogers⁶  Michael Field⁶  Lorena Santa Maria⁷  Paulina Morales⁷  Victor Faundes⁷  Bianca Curotto⁷  Cesar Trigo⁷  Angelica M. Alliende⁷  Isabel Salas⁷  Matthew F. Hunter⁸  Kim Cornish⁹  David Francis^1,10  Justine Elliott^1,10 

[1] Brain and Mind, Murdoch Children’s Research Institute, Royal Children’s Hospital;Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne;Department of Paediatrics, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne;Diagnosis and Development, Murdoch Children’s Research Institute, Royal Children’s Hospital;Fragile X Alliance Inc, North Caulfield, VIC and Center for Developmental Disability Health Victoria, Monash University;Genetics of Learning Disability Service, Hunter Genetics;Molecular and Cytogenetics Laboratory, INTA, University of Chile;Monash Genetics, Monash Health;Monash Institute of Cognitive and Clinical Neurosciences, Monash University;Victorian Clinical Genetics Services and Murdoch Children’s Research Institute, Royal Children’s Hospital;

关键词: Fragile X syndrome;    FMR1 mRNA;    Autism;    Intellectual disability;    Mosaicism;   

DOI  :  10.1186/s13229-019-0271-7

来源: DOAJ

【 摘 要 】

Abstract Background Fragile X syndrome (FXS) is a common monogenic cause of intellectual disability with autism features. While it is caused by loss of the FMR1 product (FMRP), mosaicism for active and inactive FMR1 alleles, including alleles termed premutation (PM: 55–199 CGGs), is not uncommon. Importantly, both PM and active full mutation (FM: ≥ 200 CGGs) alleles often express elevated levels of mRNA that are thought to be toxic. This study determined if complete FMR1 mRNA silencing from FM alleles and/or levels of FMR1 mRNA (if present) in blood are associated with intellectual functioning and autism features in FXS. Methods The study cohort included 98 participants (70.4% male) with FXS (FM-only and PM/FM mosaic) aged 1–43 years. A control group of 14 females were used to establish control FMR1 mRNA reference range. Intellectual functioning and autism features were assessed using the Mullen Scales of Early Learning or an age-appropriate Wechsler Scale and the Autism Diagnostic Observation Schedule-2nd Edition (ADOS-2), respectively. FMR1 mRNA was analysed in venous blood collected at the time of assessments, using the real-time PCR relative standard curve method. Results Females with FXS had significantly higher levels of FMR1 mRNA (p < 0.001) than males. FMR1 mRNA levels were positively associated with age (p < 0.001), but not with intellectual functioning and autistic features in females. FM-only males (aged < 19 years) expressing FM FMR1 mRNA had significantly higher ADOS calibrated severity scores compared to FM-only males with completely silenced FMR1 (p = 0.011). However, there were no significant differences between these subgroups on intellectual functioning. In contrast, decreased levels of FMR1 mRNA were associated with decreased intellectual functioning in FXS males (p = 0.029), but not autism features, when combined with the PM/FM mosaic group. Conclusion Incomplete silencing of toxic FM RNA may be associated with autistic features, but not intellectual functioning in FXS males. While decreased levels of mRNA may be more predictive of intellectual functioning than autism features. If confirmed in future studies, these findings may have implications for patient stratification, outcome measure development, and design of clinical and pre-clinical trials in FXS.

【 授权许可】

Unknown