Fragile X syndrome

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The fragile site is visible at the bottom end of the chromosome

The fragile X syndrome (FXS) is a condition which causes mental retardation and is the most common form of retardation related to inheritance. It is named "fragile X" because of the appearance of the X chromosome when the mutation is present. This mutation affects the Fragile Mental Retardation 1 gene (FMR-1 gene) at the locus Xq 27.3. This gene contains tandem CGG trinucleotide repeats. The number of trinucleotide CGG repeats present determines whether an individual will be mentally retarded or not. There are many possible ways concerning the distribution of the number of trinucleotides, but the distribution[1] according to “The National Fragile X Foundation”[2] is as follows:

  1. Normal Population: 5 – 45 CGG repeats
  2. Grey Zone: 45 – 54 CGG repeats
  3. Premutation: 55 – 200 CGG repeats
  4. Full Mutation: 200< CGG repeats

Normal Population is the people who are not affected. The definition of the Grey Zone is “alleles unidentified as to their behaviour to the next generation”, which are still healthy individuals. In premutation, carriers can be affected with Fragile X Associated Tremor Ataxia Syndrome (FRAXTA)[3]. In males this condition causes tremors and resembles Parkinson after exceeding a certain age (approximately 50 years old), while in women this condition causes Premature Ovarian Insufficiency (POI) [4], meaning menopause comes earlier than the 40 years of age. Full Mutation is, of course, when the individual has the symptoms of the syndrome, like a low IQ score, but also visible characteristics, such as an elongated face, large and prominent ears, strabismus (misalignment of the eyes) and others.

The arrow shows the location of the FMR-1 gene

Causes of trinucleotide repeats

The cause of FXS is the expansion of the CGG repeats. There have been a number of assumptions on how this happens. The most probable one is that there is an extension when the DNA is replicated[5]. DNA polymerase pauses at 29-31 CGG repeats, but is nevertheless close to the threshold of 34 repeats. During replication, when close to the threshold, a hairpin structure or a loop might be created and thus, leading to an expansion of the CGG repeats.


  4. Rodriguez-Revenga L, Madrigal I, Pagonabarraga J, Xunclà M, Badenas C, Kulisevsky J, et al. (2009) Penetrance of FMR1 premutation associated pathologies in fragile X syndrome families. Eur J Hum Genet. 17: 1359-62.
  5. de Graaf, Esther (1996) The Fragile X Syndrome; Complex Behavior Of A Simple Repeat. PhD Thesis, Erasmus University, Rotterdam.
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