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Tissue mosaicism,FMR1 expression and intellectual functioning in males with fragile X syndrome |
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| Authors: | Emma K. Baker Marta Arpone Minh Bui Claudine M. Kraan Ling Ling David Francis Mathew F. Hunter Carolyn Rogers Michael J. Field Lorena Santa María Víctor Faundes Bianca Curotto Paulina Morales Cesar Trigo Isabel Salas Angelica M. Alliende David J. Amor David E. Godler |
| Affiliation: | 1. Diagnosis and Development, Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, Victoria, Australia Department of Paediatrics, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Victoria, Australia School of Psychology and Public Health, La Trobe University, Bundoora, Victoria, Australia;2. Diagnosis and Development, Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, Victoria, Australia;3. Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Victoria, Australia;4. Victorian Clinical Genetics Services and Murdoch Children's Research Institute, The Royal Children's Hospital, Melbourne, Victoria, Australia;5. Monash Genetics, Monash Health, Clayton, Victoria, Australia;6. Genetics of Learning Disability Service, Hunter Genetics, Waratah, New South Wales, Australia;7. Molecular and Cytogenetics Laboratory, INTA University of Chile, Santiago, Chile;8. Department of Paediatrics, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Victoria, Australia |
| Abstract: | Fragile X syndrome (FXS) is caused by hypermethylation of the FMR1 promoter due to the full mutation expansion (full mutation [FM]: CGG ≥ 200 repeats) and silencing of FMR1. Assessment of mosaicism for active-unmethylated alleles has prognostic utility. This study examined relationships between FMR1 methylation in different tissues with FMR1 messenger ribonucleic acid (mRNA) and intellectual functioning in 87 males with FXS (1.89–43.17 years of age). Methylation sensitive Southern blot (mSB) and Methylation Specific-Quantitative Melt Aanalysis (MS-QMA) were used to examine FMR1 methylation. FMR1 mRNA levels in blood showed strong relationships with FMR1 methylation assessed using MS-QMA in blood (n = 68; R2 = 0.597; p = 1.4 × 10−10) and buccal epithelial cells (BEC) (n = 62; R2 = 0.24; p = 0.003), with these measures also showing relationships with intellectual functioning scores (p < 0.01). However, these relationships were not as strong for mSB, with ~40% of males with only FM alleles that were 100% methylated and non-mosaic by mSB, showing methylation mosaicism by MS-QMA. This was confirmed through presence of detectable levels of FMR1 mRNA in blood. In summary, FMR1 methylation levels in blood and BEC examined by MS-QMA were significantly associated with FMR1 mRNA levels and intellectual functioning in males with FXS. These relationships were not as strong for mSB, which underestimated prevalence of mosaicism. |
| Keywords: | DNA methylation epigenetics FMR1 fragile X syndrome intellectual disability mosaicism |