Methylation of novel markers of fragile X alleles is inversely correlated with FMRP expression and FMR1 activation ratio

Godler, David E., Tassone, Flora, Loesch, Danuta Z., Taylor, Annette Kimball, Gehling, Freya, Hagerman, Randi Jenssen, Burgess, Trent, Ganesamoorthy, Devika, Hennerich, Debbie, Gordon, Lavinia, Evans, Andrew, Choo, K. H. and Slater, Howard Robert (2010) Methylation of novel markers of fragile X alleles is inversely correlated with FMRP expression and FMR1 activation ratio. Human Molecular Genetics, 19 8: 1618-1632. doi:10.1093/hmg/ddq037


Author Godler, David E.
Tassone, Flora
Loesch, Danuta Z.
Taylor, Annette Kimball
Gehling, Freya
Hagerman, Randi Jenssen
Burgess, Trent
Ganesamoorthy, Devika
Hennerich, Debbie
Gordon, Lavinia
Evans, Andrew
Choo, K. H.
Slater, Howard Robert
Title Methylation of novel markers of fragile X alleles is inversely correlated with FMRP expression and FMR1 activation ratio
Journal name Human Molecular Genetics   Check publisher's open access policy
ISSN 0964-6906
1460-2083
Publication date 2010-01-29
Year available 2010
Sub-type Article (original research)
DOI 10.1093/hmg/ddq037
Open Access Status
Volume 19
Issue 8
Start page 1618
End page 1632
Total pages 15
Place of publication Oxford, United Kingdom
Publisher Oxford University Press
Collection year 2010
Language eng
Subject 1311 Genetics
2716 Genetics (clinical)
1312 Molecular Biology
Abstract The fragile X syndrome (FXS) is caused by silencing of the fragile X mental retardation gene (FMR1) and the absence of its product, fragile X mental retardation protein (FMRP), resulting from CpG island methylation associated with large CGG repeat expansions (more than 200) termed full mutation (FM). We have identified a number of novel epigenetic markers for FXS using matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS), naming the most informative fragile X-related epigenetic element 1 (FREE1) and 2 (FREE2). Methylation of both regions was correlated with that of the FMR1 CpG island detected using Southern blot (FREE1 R = 0.97; P < 0.00001, n = 23 and FREE2 R = 0.93; P < 0.00001, n = 23) and nega- tively correlated with lymphocyte expression of FMRP (FREE1 R 520.62; P = 0.01, n = 15 and FREE2 R 520.55; P = 0.03, n = 15) in blood of partially methylated 'high functioning' FM males. In blood of FM carrier females, methylation of both markers was inversely correlated with the FMR1 activation ratio (FREE1 R 520.93; P < 0.0001, n = 12 and FREE2 R 520.95; P < 0.0001, n = 9). In a sample set of 49 controls, 18 grey zone (GZ 40-54 repeats), 22 premutation (PM 55-170 repeats) and 22 (affected) FXS subjects, the FREE1 methylation pattern was consistent between blood and chorionic villi as a marker of methylated FM alleles and could be used to differentiate FXS males and females from controls, as well as from carriers of GZ/PM alleles, but not between GZ and PM alleles and controls. Considering its high-throughput and speci- ficity for pathogenic FM alleles, low cost and minimal DNA requirements, FREE MALDI-TOF MS offers a unique tool in FXS diagnostics and newborn population screening.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Institute for Molecular Bioscience - Publications
 
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