Genetics and Transmission

GENETICS

Fragile X Syndrome has a genetic origin and is hereditary. It is caused by mutations in the FMR1 gene (fragile x messenger ribonucleoprotein 1). This gene is responsible for producing the FMRP protein (Fragile Mental Retardation Protein), which helps to regulate the production of other proteins that affect the development of important nervous system connections.

Studying the chromosomes in cases of Fragile X Syndrome, we can observe a flaw in the subterminal portion of the long arm of the X chromosome, called the fragile site. For this reason, this condition is called FRAGILE X SYNDROME.

The mechanism that causes the mutation present in Fragile X Syndrome is the increase of copies of Cytosine-Guanine-Guanine (CGC), that is, the amount of DNA is increased at the site of the FMR1 gene.

In people who do not have FXS, the number of CGG repeats ranges from 6 to 39. In people affected by the Syndrome, the CGG segment repeats more than 200 times. This causes the FMR1 gene to “shut down”, which prevents the production of the FMRP protein. The loss of this protein interferes with the functions of the nervous system and gives rise to the characteristics of the Fragile X Syndrome.

Men and women with repetitions of the CGG segment between 55 and 200 are carriers of FXS and are called pre-mutated. At this stage, the altered gene is active and these people, in general, have no symptoms. As it is transmitted, the pre-mutation tends to evolve to the complete mutation, and, at this stage, the gene stops working.

If the person is male, he will have Fragile X Syndrome. If female, she may or may not be affected, because, in addition to the X chromosome with the complete mutation, she has the healthy FMR1 gene on the other X chromosome. This may, or may not, be enough for the symptoms of the syndrome not to occur. Therefore, in girls, FXS is less severe than in boys, or it may not even manifest itself.

TRANSMISSION

(by Martha Carvalho)

Women with pre-mutation on one of their X chromosomes can transmit the normal or altered FMR1 gene, with equal probability, to their sons and daughters. The altered gene can be transmitted as a pre-mutation or evolve to a complete mutation. Thus, both daughters and sons of women with pre-mutation have a 50% chance of receiving the X chromosome whose FMR1 gene is normal. But, if they inherit the X chromosome whose FMR1 gene is altered, they may have the pre-mutation or the complete mutation.

Women who have a complete mutation on one of their X chromosomes are 50% likely to transmit that complete mutation or the X chromosome with the normal FMR1 gene to their sons and daughters. If they inherit the complete mutation, they may be affected by Fragile X Syndrome.

Men carrying the pre-mutation will transmit the altered gene to all daughters and they will also have the pre-mutation. Transmitted from father to daughter, the premutation does not turn into a full mutation (Oberlé et al., 1991: Yu et al., 1991). Therefore, the daughters of men with the pre-mutation are not affected by Fragile X Syndrome.

Men affected by FXS, therefore with the complete mutation, will transmit the altered gene to all daughters. However, unlike expected, the affected father’s X chromosome will go to the daughters only with the pre-mutation and not with the complete mutation (Willems et al., 1992). Somehow, the complete mutation regresses to pre-mutation and the sperm of the affected individuals only have the pre-mutation (Reyniers et al., 1993).

CARVALHO, M. Fragile X Syndrome – Guide for families and professionals. Ed. Brazilian Society of Genetics, 2004. (Pages 11 and 12)

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