%0 Journal Article
%T FRA2A Is a CGG Repeat Expansion Associated with Silencing of AFF3
%A Chandra Sekhar Reddy Chilamakuri
%A David I. Wilson
%A David R. FitzPatrick
%A Edwin Reyniers
%A Eric Haan
%A Evelyn Douglas
%A Geert Vandeweyer
%A Geoffrey Thompson
%A Harris Morrison
%A Hemant Bengani
%A Jacqueline Rainger
%A Jozef Gecz
%A Liesbeth Rooms
%A Martin S. Taylor
%A R. Frank Kooy
%A Sofie Metsu
%J -
%D 2014
%R 10.1371/journal.pgen.1004242
%X Folate-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¨C12.5dpc 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
%K DNA methylation
%K Polymerase chain reaction
%K DNA sequence analysis
%K Repeated sequences
%K DNA transcription
%K Alleles
%K Genomic libraries
%K Mammalian genomics
%U https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1004242