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Mechanisms of disease

The discovery of simple repeats that cause complex disorders

Nature Reviews Molecular Cell Biology volume 25, page 161 (2024)Cite this article

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In 1991, an international group of scientists identified the gene and DNA sequence at the X chromosome that underly the disease fragile X syndrome (FXS) and its associated chromosomal fragility. This landmark study found that expansion of a simple (CGG) repeat, in this case located in the 5’ region of the recently renamed FMR1 (fragile X messenger ribonucleoprotein 1) gene, could cause a human disorder.

Subsequently, it was shown that sequence expansions beyond 200 CGG repeats (‘full mutation’) lead to DNA methylation and silencing of FMR1. Later, it was revealed that FMR1 is an RNA-binding protein that is essential for cellular functions such as synaptic plasticity. Consequently, individuals with FXS exhibit a range of symptoms, including intellectual disabilities and autism.

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References

Original article

  • Verkerk, A. J. M. H. et al. Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome. Cell 65, 905–914 (1991)

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Related article

  • La Spada, A. R. et al. Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy. Nature 352, 77–79 (1991)

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Authors and Affiliations

  1. Center for Reproductive Medicine, Department of Obstetrics & Gynecology, Weill Cornell Medicine, New York, USA

    Jeannine Gerhardt

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  1. Jeannine Gerhardt
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Correspondence to Jeannine Gerhardt.

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Gerhardt, J. The discovery of simple repeats that cause complex disorders. Nat Rev Mol Cell Biol 25, 161 (2024). https://doi.org/10.1038/s41580-023-00666-z

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