Fragile X syndrome is a very common form of inherited mental retardation. To understand the disease, it is first important to realise that some chromosomes contain the so-called fragile sites. Fragile sites are regions of the chromosome that can form gaps or constrictions that may break under certain conditions. Some fragile sites are very common and are present in all individuals. Rare fragile sites, on the other hand, can be associated with human genetic disorders.
One of these fragile sites is located on the X chromosome and contains a trinucleotide repeat CGG. This trinucleotide is part of the FMR-1 gene (fragile X mental retardation gene 1). The copies of the trinucleotide in the gene increase in number over time - a normal FMR-1 gene contains 6 to 69 copies of the repeat, but abnormal FMR-1 genes can contain up to 1500 copies of the trinucleotide. Mutations that increase in the number of copies of a set of nucleotides are generally called expanding nucleotide repeats. This increased number of CGG copies turns off the transcription of the FMR-1 gene, which stops the synthesis of the protein product of the gene – FMRP protein. This leads to mental deficiencies. In addition to mental retardation, affected males have long, narrow faces, a prominent forehead, enlarged ears, and increased testicular size. The exact mechanism that causes the increase in the trinucleotide repeats is yet unknown.
What is also interesting is that parents can transmit the gene with an increased number of the CGG repeats to their offspring. As the number of the repeats increases in each generation and eventually causes the fragile X syndrome, the phenomenon is called genetic anticipation.
References:
Klug, W. S., Cummings, M. R., Spencer, C. A., Palladino, M. A., & Killian, D. (2019). Concepts of Genetics. Pearson.
Pierce, B. A. (2019). Genetics: A Conceptual Approach (Seventh ed.). W. H. Freeman.
Snustad, D. P., & Simmons, M. J. (2012). Principles of Genetics. Wiley