Tissue mosaicism, FMR1 expression and intellectual functioning in males with fragile X syndrome.

Autor: Baker EK; 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., Arpone M; 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.; Brain and Mind, Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Victoria, Australia., Bui M; Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Victoria, Australia., Kraan CM; 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., Ling L; Diagnosis and Development, Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, Victoria, Australia., Francis D; Victorian Clinical Genetics Services and Murdoch Children's Research Institute, The Royal Children's Hospital, Melbourne, Victoria, Australia., Hunter MF; Monash Genetics, Monash Health, Clayton, Victoria, Australia.; Department of Paediatrics, Monash University, Clayton, Victoria, Australia., Rogers C; Genetics of Learning Disability Service, Hunter Genetics, Waratah, New South Wales, Australia., Field MJ; Genetics of Learning Disability Service, Hunter Genetics, Waratah, New South Wales, Australia., Santa María L; Molecular and Cytogenetics Laboratory, INTA University of Chile, Santiago, Chile., Faundes V; Molecular and Cytogenetics Laboratory, INTA University of Chile, Santiago, Chile., Curotto B; Molecular and Cytogenetics Laboratory, INTA University of Chile, Santiago, Chile., Morales P; Molecular and Cytogenetics Laboratory, INTA University of Chile, Santiago, Chile., Trigo C; Molecular and Cytogenetics Laboratory, INTA University of Chile, Santiago, Chile., Salas I; Molecular and Cytogenetics Laboratory, INTA University of Chile, Santiago, Chile., Alliende AM; Molecular and Cytogenetics Laboratory, INTA University of Chile, Santiago, Chile., Amor DJ; Department of Paediatrics, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Victoria, Australia.; Neurodisability and Rehabilitation, Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, Victoria, Australia., Godler DE; 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.
Jazyk: angličtina
Zdroj: American journal of medical genetics. Part A [Am J Med Genet A] 2023 Feb; Vol. 191 (2), pp. 357-369. Date of Electronic Publication: 2022 Nov 08.
DOI: 10.1002/ajmg.a.63027
Abstrakt: 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; R 2  = 0.597; p = 1.4 × 10 -10 ) and buccal epithelial cells (BEC) (n = 62; R 2  = 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.
(© 2022 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)
Databáze: MEDLINE
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