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Disease genetics

Twin-track approach to fragile X

Nature Reviews Genetics volume 3, page 4 (2002)Cite this article

The study by Victoria Brown, Peng Jin and colleagues involved two microarray experiments. In the first, mRNA isolated from mouse brain was compared with mRNA that had been immunoprecipitated with an FMR1 antibody, the aim being to find mRNA that was bound to FMR1. Of the >25,000 genes screened, 432 were identified that were enriched by immunoprecipitation. The second study compared polysomal RNA from fragile X with control human cell lines. The authors reasoned that if FMR1 regulates translation by binding to polysomal RNA, the absence of FMR1 in the fragile X cell lines should lead to differences in the abundance of specific polysome-associated RNAs. In this experiment, >35,000 genes were compared, and 251 showed substantial differences in abundance between the polysomal RNA fractions of the fragile X and control cell lines. A partial comparison of the sets of genes revealed 14 that were identified in both experiments, and could therefore be targets for regulation by FMR1.

The second paper reports a biochemical approach to finding the optimal RNA target sequence for FMR1. After several rounds of selection from a pool of random RNA sequences, Jennifer Darnell et al. identified an RNA molecule that bound to FMR1 with high affinity. They then defined the minimal sequence required for binding, and concluded that FMR1 requires a specific RNA structure called a G quartet, which is present in only a small percentage of transcripts. They tested 12 such transcripts for binding to FMR1, and found six that bound. So, there is more to find out about the requirements for FMR1 binding, but the presence of a G quartet is a good pointer.

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References

ORIGINAL RESEARCH PAPERS

  1. Brown, V. et al. Microarray identification of FMRP-associated brain mRNAs and altered mRNA translational profiles in fragile X syndrome. Cell 107, 477–487 (2001)

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  2. Darnell, J. C. et al. Fragile X mental retardation protein targets G quartet mRNAs important for neuronal function. Cell 107, 489–499 (2001)

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FURTHER READING

  1. Chelly, J. & Mandel, J.-L. Monogenic causes of X-linked mental retardation. Nature Rev. Genet. 2, 669–680 (2001)

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Authors
  1. Mark Patterson
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Patterson, M. Twin-track approach to fragile X. Nat Rev Genet 3, 4 (2002). https://doi.org/10.1038/nrg719

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