Medicine:Fragile mental retardation 2
Fragile mental retardation 2 is a gene (FMR2: synonym AFF2), located on the human X chromosome. Mutations in this gene are associated with X-linked intellectual disability and specifically a syndrome known as fragile X E syndrome (FRAXE).[1] FRAXE is one of the most common forms of non-syndromic X-linked mental retardation. The most common mutation giving rise to this syndrome is a triplet expansion of CCG in the 5' untranslated region which leads to a silencing of the gene. Mutations within the gene may also cause this phenotype.
Genomics
This gene is located on the long arm of chromosome X (Xq27.3-Xq28) It has 22 exons spanning at least 500 kb. Alternative splicing may occur and involve exons 2, 3, 5, 7 and 21. The normal encoded protein is 1311 codons in length. It is expressed as an 8.7 kilobase transcript in the placenta and adult brain.
The normal 5' untranslated region has 10-35 CCG repeats and more frequently 15-20. Pathogenic expansions have typically over 200 repeats and are methylated.
This gene belongs to the AFF family of genes which currently has four members: AFF1/AF4, AFF2/FMR2, AFF3/LAF4 and AFF4/AF5q31.[2] All AFF proteins are localized in the nucleus and have a role as transcriptional activators with a positive action on RNA elongation. AFF2/FMR2, AFF3/LAF4 and AFF4/AF5q31 localize in nuclear speckles (subnuclear structures considered to be storage/modification sites of pre-mRNA splicing factors) and are able to bind RNA with a high apparent affinity for the G-quadruplex structure. They appear to modulate alternative splicing via the interaction with the G-quadruplex RNA-forming structure.
The other members of this family have been reported to form fusion genes as a consequence of chromosome translocations and are involved in the pathogenesis of myeloid/lymphoid or mixed lineage leukemia.
A Drosophila FMR2 orthologue Lilliputian (Lilli) has been identified.
References
- ↑ Stettner GM, Shoukier M, Höger C, Brockmann K, Auber B (2011) Familial intellectual disability and autistic behavior caused by a small FMR2 gene deletion. Am J Med Genet A. doi:10.1002/ajmg.a.34122
- ↑ Melko M, Douguet D, Bensaid M, Zongaro S, Verheggen C, Gecz J, Bardoni B (2011) Functional characterization of the AFF (AF4/FMR2) family of RNA-binding proteins: insights into the molecular pathology of FRAXE intellectual disability. Hum Mol Genet. 2011 May 15;20(10):1873-1885
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