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

被引：5

作者：

Baker, Emma K. ^{[1
,2
,3
]}

Arpone, Marta ^{[1
,2
,4
]}

Minh Bui ^{[5
]}

Kraan, Claudine M. ^{[1
,2
]}

Ling, Ling ^{[1
]}

Francis, David ^{[6
,7
]}

Hunter, Mathew F. ^{[8
,9
]}

Rogers, Carolyn ^{[10
]}

Field, Michael J. ^{[10
]}

Santa Maria, Lorena ^{[11
]}

Faundes, Victor ^{[11
]}

Curotto, Bianca ^{[11
]}

Morales, Paulina ^{[11
]}

Trigo, Cesar ^{[11
]}

Salas, Isabel ^{[11
]}

Alliende, Angelica M. ^{[11
]}

Amor, David J. ^{[2
,12
]}

Godler, David E. ^{[1
,2
]}

机构：

[1] Royal Childrens Hosp, Murdoch Childrens Res Inst, Diag & Dev, Melbourne, Vic, Australia

[2] Univ Melbourne, Fac Med Dent & Hlth Sci, Dept Paediat, Parkville, Vic, Australia

[3] La Trobe Univ, Sch Psychol & Publ Hlth, Bundoora, Vic, Australia

[4] Royal Childrens Hosp, Murdoch Childrens Res Inst, Brain & Mind, Parkville, Vic, Australia

[5] Univ Melbourne, Ctr Epidemiol & Biostat, Melbourne Sch Populat & Global Hlth, Melbourne, Vic, Australia

[6] Royal Childrens Hosp, Victorian Clin Genet Serv, Melbourne, Vic, Australia

[7] Royal Childrens Hosp, Murdoch Childrens Res Inst, Melbourne, Vic, Australia

[8] Monash Hlth, Monash Genet, Clayton, Vic, Australia

[9] Monash Univ, Dept Paediat, Clayton, Vic, Australia

[10] Genet Learning Disabil Serv, Hunter Genet, Waratah, NSW, Australia

[11] INTA Univ Chile, Mol & Cytogenet Lab, Santiago, Chile

[12] Royal Childrens Hosp, Murdoch Childrens Res Inst, Neurodisabil & Rehabil, Melbourne, Vic, Australia

来源：

AMERICAN JOURNAL OF MEDICAL GENETICS PART A | 2023年 / 191卷 / 02期

基金：

英国医学研究理事会; 澳大利亚国家健康与医学研究理事会;

关键词：

DNA methylation; epigenetics; FMR1; fragile X syndrome; intellectual disability; mosaicism; FULL-MUTATION ALLELES; FEMALE CARRIERS; DIRECT DIAGNOSIS; METHYLATION; GENE; IDENTIFICATION; BLOOD; AGE; INDIVIDUALS; SELECTION;

D O I：

10.1002/ajmg.a.63027

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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 x 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 similar to 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.

引用

页码：357 / 369

页数：13

共 42 条

[1] Identification of Males with Cryptic Fragile X Alleles by Methylation-Specific Quantitative Melt Analysis [J].

Aliaga, Solange M. ;

Slater, Howard R. ;

Francis, David ;

Du Sart, Desiree ;

Li, Xin ;

Amor, David J. ;

Alliende, Angelica M. ;

Santa Maria, Lorena ;

Faundes, Victor ;

Morales, Paulina ;

Trigo, Cesar ;

Salas, Isabel ;

Curotto, Bianca ;

Godler, David E. .

CLINICAL CHEMISTRY, 2016, 62 (02) :343-352

[2]

Alliende MA, 1998, REV MED CHILE, V126, P1435

[3] Intragenic DNA methylation in buccal epithelial cells and intellectual functioning in a paediatric cohort of males with fragile X [J].

Arpone, Marta ;

Baker, Emma K. ;

Bretherton, Lesley ;

Bui, Minh ;

Li, Xin ;

Whitaker, Simon ;

Dissanayake, Cheryl ;

Cohen, Jonathan ;

Hickerton, Chriselle ;

Rogers, Carolyn ;

Field, Mike ;

Elliott, Justine ;

Aliaga, Solange M. ;

Ling, Ling ;

Francis, David ;

Hearps, Stephen J. C. ;

Hunter, Matthew F. ;

Amor, David J. ;

Godler, David E. .

SCIENTIFIC REPORTS, 2018, 8

[4] Incomplete silencing of full mutation alleles in males with fragile X syndrome is associated with autistic features [J].

Baker, Emma K. ;

Arpone, Marta ;

Aliaga, Solange M. ;

Bretherton, Lesley ;

Kraan, Claudine M. ;

Minh Bui ;

Slater, Howard R. ;

Ling, Ling ;

Francis, David ;

Hunter, Matthew F. ;

Elliott, Justine ;

Rogers, Carolyn ;

Field, Michael ;

Cohen, Jonathan ;

Cornish, Kim ;

Santa Maria, Lorena ;

Faundes, Victor ;

Curotto, Bianca ;

Morales, Paulina ;

Trigo, Cesar ;

Salas, Isabel ;

Alliende, Angelica M. ;

Amor, David J. ;

Godler, David E. .

MOLECULAR AUTISM, 2019, 10 (1)

[5] EMQN best practice guidelines for the molecular genetic testing and reporting of fragile X syndrome and other fragile X-associated disorders [J].

Biancalana, Valerie ;

Glaeser, Dieter ;

McQuaid, Shirley ;

Steinbach, Peter .

EUROPEAN JOURNAL OF HUMAN GENETICS, 2015, 23 (04) :417-425

[6] A Genotype-Phenotype Study of High-Resolution FMR1 Nucleic Acid and Protein Analyses in Fragile X Patients with Neurobehavioral Assessments [J].

Budimirovic, Dejan B. ;

Schlageter, Annette ;

Filipovic-Sadic, Stela ;

Protic, Dragana D. ;

Bram, Eran ;

Mahone, E. Mark ;

Nicholson, Kimberly ;

Culp, Kristen ;

Javanmardi, Kamyab ;

Kemppainen, Jon ;

Hadd, Andrew ;

Sharp, Kevin ;

Adayev, Tatyana ;

LaFauci, Giuseppe ;

Dobkin, Carl ;

Zhou, Lili ;

Brown, William Ted ;

Berry-Kravis, Elizabeth ;

Kaufmann, Walter E. ;

Latham, Gary J. .

BRAIN SCIENCES, 2020, 10 (10) :1-25

[7] Epigenetic Characterization of the FMR1 Promoter in Induced Pluripotent Stem Cells from Human Fibroblasts Carrying an Unmethylated Full Mutation [J].

de Esch, Celine E. F. ;

Ghazvini, Mehrnaz ;

Loos, Friedemann ;

Schelling-Kazaryan, Nune ;

Widagdo, W. ;

Munshi, Shashini T. ;

van der Wal, Erik ;

Douben, Hannie ;

Gunhanlar, Nilhan ;

Kushner, Steven A. ;

Pijnappel, W. W. M. Pim ;

de Vrij, Femke M. S. ;

Geijsen, Niels ;

Gribnau, Joost ;

Willemsen, Rob .

STEM CELL REPORTS, 2014, 3 (04) :548-555

[8]

deVries BBA, 1996, AM J HUM GENET, V58, P1025

[9] Significantly Elevated FMR1 mRNA and Mosaicism for Methylated Premutation and Full Mutation Alleles in Two Brothers with Autism Features Referred for Fragile X Testing [J].

Field, Michael ;

Dudding-Byth, Tracy ;

Arpone, Marta ;

Baker, Emma K. ;

Aliaga, Solange M. ;

Rogers, Carolyn ;

Hickerton, Chriselle ;

Francis, David ;

Phelan, Dean G. ;

Palmer, Elizabeth E. ;

Amor, David J. ;

Slater, Howard ;

Bretherton, Lesley ;

Ling, Ling ;

Godler, David E. .

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, 2019, 20 (16)

[10]

Francis D, 2000, MOL DIAGN, V5, P221, DOI 10.2165/00066982-200005030-00008

← 1 2 3 4 5 →