Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/94789
Citations
Scopus Web of Science® Altmetric
?
?
Full metadata record
DC FieldValueLanguage
dc.contributor.authorMetsu, S.en
dc.contributor.authorRooms, L.en
dc.contributor.authorRainger, J.en
dc.contributor.authorTaylor, M.en
dc.contributor.authorBengani, H.en
dc.contributor.authorWilson, D.en
dc.contributor.authorChilamakuri, C.en
dc.contributor.authorMorrison, H.en
dc.contributor.authorVandeweyer, G.en
dc.contributor.authorReyniers, E.en
dc.contributor.authorDouglas, E.en
dc.contributor.authorThompson, G.en
dc.contributor.authorHaan, E.en
dc.contributor.authorGecz, J.en
dc.contributor.authorFitzPatrick, D.en
dc.contributor.authorKooy, R.en
dc.date.issued2014en
dc.identifier.citationPLoS Genetics, 2014; 10(4):e1004242-1-e1004242-14en
dc.identifier.issn1553-7404en
dc.identifier.issn1553-7404en
dc.identifier.urihttp://hdl.handle.net/2440/94789-
dc.description.abstractFolate-sensitive fragile sites (FSFS) are a rare cytogenetically visible subset of dynamic mutations. Of the eight molecularly characterized FSFS, four are associated with intellectual disability (ID). Cytogenetic expression results from CGG tri-nucleotide-repeat expansion mutation associated with local CpG hypermethylation and transcriptional silencing. The best studied is the FRAXA site in the FMR1 gene, where large expansions cause fragile X syndrome, the most common inherited ID syndrome. Here we studied three families with FRA2A expression at 2q11 associated with a wide spectrum of neurodevelopmental phenotypes. We identified a polymorphic CGG repeat in a conserved, brain-active alternative promoter of the AFF3 gene, an autosomal homolog of the X-linked AFF2/FMR2 gene: Expansion of the AFF2 CGG repeat causes FRAXE ID. We found that FRA2A-expressing individuals have mosaic expansions of the AFF3 CGG repeat in the range of several hundred repeat units. Moreover, bisulfite sequencing and pyrosequencing both suggest AFF3 promoter hypermethylation. cSNP-analysis demonstrates monoallelic expression of the AFF3 gene in FRA2A carriers thus predicting that FRA2A expression results in functional haploinsufficiency for AFF3 at least in a subset of tissues. By whole-mount in situ hybridization the mouse AFF3 ortholog shows strong regional expression in the developing brain, somites and limb buds in 9.5-12.5dpc mouse embryos. Our data suggest that there may be an association between FRA2A and a delay in the acquisition of motor and language skills in the families studied here. However, additional cases are required to firmly establish a causal relationship.en
dc.description.statementofresponsibilitySofie Metsu, Liesbeth Rooms, Jacqueline Rainger, Martin S. Taylor, Hemant Bengani, David I. Wilson, Chandra Sekhar Reddy Chilamakuri, Harris Morrison, Geert Vandeweyer, Edwin Reyniers, Evelyn Douglas, Geoffrey Thompson, Eric Haan, Jozef Gecz, David R. FitzPatrick, R. Frank Kooyen
dc.language.isoenen
dc.publisherPublic Library of Scienceen
dc.rights© 2014 Metsu et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.en
dc.subjectHumans; Nuclear Proteins; DNA Methylation; Gene Expression; Trinucleotide Repeat Expansion; Phenotype; Polymorphism, Single Nucleotide; Alleles; Chromosome Fragile Sites; Female; Male; Fos-Related Antigen-2; Promoter Regions, Genetic; Intellectual Disabilityen
dc.titleFRA2A is a CGG repeat expansion associated with silencing of AFF3en
dc.typeJournal articleen
dc.identifier.rmid0030009036en
dc.identifier.doi10.1371/journal.pgen.1004242en
dc.identifier.pubid91746-
pubs.library.collectionPaediatrics publicationsen
pubs.library.teamDS01en
pubs.verification-statusVerifieden
pubs.publication-statusPublisheden
dc.identifier.orcidHaan, E. [0000-0002-7310-5124]en
dc.identifier.orcidGecz, J. [0000-0002-7884-6861]en
Appears in Collections:Paediatrics publications

Files in This Item:
File Description SizeFormat 
hdl_94789.pdfPublished version1.98 MBAdobe PDFView/Open


Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.