Fragile XE mental retardation (also referred to as fragile XE syndrome) is an X-linked dominant disorder that is defined by patients who have the cytogenetic changes associated with fragile X syndrome but who are FMR1 mutation negative (FMR1 is the gene affected in fragile X syndrome). Fragile XE mental retardation results from the expansion of a CCG trinucleotide repeat in the 5'-untranslated region (UTR) of the fragile X mental retardation 2 (FMR2) locus. The affected gene at this locus is known as the AF4/FMR2 family, member 2 (AFF2) gene . Normal individuals have 4 to 39 CCG repeats whereas in affected individuals the repeat size is 200 to 900. When the CCG repeat is expanded the site is referred to as the FRAXE fragile site. Expansion of the CCG repeat leads to hypermethylation and consequent transcriptional silencing of the AFF2 gene such that no protein is produced in affected individuals.
Fragile XE mental retardation syndrome belongs to a family of disorders that are related to the relationship between fragile chromosomal sites and disease. Fragile chromosomal sites are only detectable in vitro when cells are exposed to chemical agents that disrupt the DNA replication process. To date 30 rare and 89 common fragile chromosome sites have been identified. Common sites are considered to be present in all individuals, whereas, rare sites are found only in a small percentage of persons. The majority of the rare fragile sites are folate-sensitive and are so defined because they present when cells are cultured in folate-deficient media or in the presence of inhibitors of folate metabolism. The fragile XE mental retardation locus (FRAXE) belongs to the class of folate-sensitive rare fragile sites. The majority of the common fragile sites are detectable by the addition of aphidicolin to cell cultures. Aphidicolin is an inhibitor of DNA polymerase.
The AFF2 gene is located on the X chromosome at Xq28 spanning at least 500 kb and composed of 22 exons that generate six alternatively spliced mRNAs. The AFF2 gene resides approximately 600 kb distal to the FMR1 gene. AFF2 is expressed in placenta, fetal brain, lung and kidney and adult brain. The AFF2 protein is a member of a family of proline- and serine-rich nuclear proteins with putative transcription transactivation function.
Clinical features of fragile XE syndrome include mild mental retardation, learning deficit and developmental delay. Some individuals afflicted with fragile XE syndrome also display autistic behaviors such as intense interest in a particular subject or object, repetitive behaviors, and hand flapping.