The fragile X mental retardation 1 (FMR1) gene is located at band Xq27.3 on the X chromosome's long arm. The gene codes for the production of fragile X mental retardation protein (FMRP), which, among other things, is believed to transport mRNA from the cytosol into the cell nucleus. The 5' untranslated region of the FMR1 gene contains a cytosine-guanine-guanine (CGG) repeat that can be categorized into four classes depending on repeat length. A normal FMR1 gene contains between 6 and 40 CGG repeats at this locus (with a mode of approximately 30). Repeat lengths greater than 200 represent the full mutation of the FMR1 gene and are the cause of fragile X syndrome, the most severely disabling of the phenotypes known to be associated with the FMR1 gene.
Persons who have between 55 and 200 CGG repeats are described as having the fragile X premutation. Unlike the full mutation phenotype, individuals with the premutation are characterized by minimal or no phenotypic anomalies. However, mutations in the premutation range are likely to undergo further expansion to the full mutation across generations.
Individuals who have CGG repeats in the range of 41 to 54 are referred to as being in the intermediate or "gray" zone. Generally, it is believed that individuals with CGG repeat expansions in this range experience no adverse effects related to the mutated gene. However, it is possible - in a small percentage of cases - for these individuals to pass on the fragile X premutation to their children.
Disorders related to the FMR1 gene are X-linked dominant disorders. The following diagram depicts the inheritance of a mutated FMR1 gene (either the full mutation or the premutation). As the fragile X gene is located on the X chromosome, transmission of the gene differs depending on the sex of the affected parent. Whereas it is impossible for a man to pass on a mutated FMR1 gene to his male child (because it resides on the X chromosome, which is not passed from father to son), an affected father will pass on the mutated gene to all of his daughters. Because women have two X chromosomes, each child of an affected mother has a 50% chance of receiving the mutated FMR1 gene. The risk of receiving the X chromosome containing the mutated gene does not differ for male and female children of an affected mother.
The number of CGG repeats in the FMR1 gene can increase across generations. Expansion in the size of the mutation tends to occur when the mutated gene is passed down from an affected mother. The trinucleotide repeat expansion enlarges as it passes through female meiosis, causing the woman's fertilized ova to have an increased probability of containing the full mutation. Hence, a woman with the premutation often will pass a larger premutation expansion or the full mutation on to her child. A mutated FMR1 gene passed from an affected father to his daughter generally remains roughly the same size across the two generations. If the father carries the premutation, his daughter also will have the premutation allele.