New insight into fragile X syndrome: Scientists identify possible link to RNAi
Two independent research groups, led by Drs. Haruhiko Siomi (Institute for Genome Research, University of Tokushima, Japan) and Gregory Hannon (Cold Spring Harbor Laboratory, USA) have discovered that the Drosophila version of the human fragile X mental retardation protein associates with components of the RNAi pathway, suggesting that the molecular mechanism underlying fragile X syndrome may involve an RNAi-related process.
“It has been our feeling since we became involved in the field several years ago that only through an understanding of the mechanism of RNAi would we be able to understand the biological implications of this process,” states Dr. Hannon.
Fragile X syndrome is the most common form of hereditary mental retardation, affecting 1 in 4000 males and 1 in 8000 females. Fragile X syndrome is the result of a genetic mutation at one end of the fragile X mental retardation 1 gene (FMR1) that causes the abnormal inactivation of the gene. It is known that the protein encoded by FMR1 — the so-called fragile X mental retardation protein (FMRP) — binds to RNA and is thought to regulate the expression of specific genes during neural development, but the mode of FMRP action in cells is yet to be defined.
This work provides some important clues.
Using Drosophila as a model organism, Drs. Siomi and Hannon and colleagues found that FMRP associates with RNAi-related cellular machinery. RNAi-induced gene silencing depends upon the introduction of double-stranded RNA, which is processed by Dicer enzymes into short pieces of double-stranded RNA. These short interfering RNAs, or siRNAs as they are known, are incorporated into an RNAi-induced silencing complex (RISC), which uses them as a guide to target and destroy complementary mRNAs, and thereby prevent synthesis of the encoded protein.
Both teams of researchers identified an association between FMRP, short double-stranded RNAs, and a previously identified subunit of RISC (a protein called AGO2); Dr. Siomi and colleagues also found that FMRP associates with the Dicer processing enzyme. These finding suggest that FMRP may function in an RNAi-related process to regulate the expression of its target genes at the level of translation (protein synthesis).
Further delineation of both the identity of FMRP target genes and how changes in their expression patterns can alter the neural landscape in such a way as to result in mental retardation are needed, but as Dr. Siomi explains, “the link between the fragile X syndrome as a phenotype and a possible role for defects in an RNAi-related apparatus through loss of the FMR1 protein will likely open up an entirely new field of molecular human genetics: defects in an RNAi-related apparatus that cause disease.”
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