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How Does the FMR1 Gene Change From Stable to Premutation to Full Mutation? A person who inherits fragile X syndrome does so as the result of a series of steps that occurred in their ancestors. The first step involves the shift from a stable version of the FMR1 (fragile X mental retardation) gene to an unstable version (premutation). This event is very rare. Once the first step has occurred, change is no longer rare. Instead it is common for someone with the premutation to pass on the full mutation to an offspring. We use the word "mutation" for an event and the result of that event. When part of the DNA is changed, that event is called a mutation. The variation that is a result of that event is also called a mutation. So we refer to a change in the number of repeats as a mutation event. We also say that someone who has more than 55 repeats has a mutation in their FMR1 gene. Stable to premutation Most people with the stable version (about 30 CGG repeats) pass on the stable version to their offspring. In other words, most people with the stable version pass on to their children, the same number of repeats that they have on their own X chromosomes. In rare cases, a person with the stable version, passes on an expanded number of repeats to the next generation. A person who has more than 55 CGG repeats has the premutation. In the children of someone with the premutation, the number of repeats is more variable than then in the children of someone with the stable version. The following general patterns have been observed. Father to sons and daughters
If a male gives an X chromosome to a child, the child will be a female. As indicated above, almost all males with the stable version have daughters with the stable version. Premutation males have premutation daughters. There may be some fluctuation up or down in the number of repeats but the number does not increase to the full mutation level. Most full mutation males (more than 200 CGG repeats) do not have children. Those few who do have children, would give their Y chromosome to their sons and their X chromosome to their daughters. The sons would not receive any version of FMR1 from the father, since the Y chromosome does not have the FMR1 gene. If these sons have a mother with the stable version, the sons would not have fragile X syndrome and would not pass it on to any of their future offspring; the only version of FMR1 they get is the stable version from mom. Those few full mutation males who do have daughters, have daughters with the premutation. This is a surprising result because they pass on a reduced number of CGG repeats to their daughters. Either, there are protected cells in the testes that never expand to the full mutation or there is a reduction in repeat number in some of the male's reproductive cells. This means that all females who do have the full mutation must have received it from their mothers since they cannot receive it from their fathers. Premutation mother to daughter
This means that half of all of the daughters of all of the premutation females will receive the premutation chromosome. However, it does not mean that each individual female will have one daughter with the premutation and one daughter with the stable version. Just as a family with two children could have two girls, two boys, or one of each, a premutation female with two daughters, could have zero, one, or two daughters with the premutation version. For those daughters who receive the stable version, the connection to fragile X is broken; they will pass the stable version on to their offspring. Most of the daughters who receive the premutation, will have more repeats than their mother had. While most will receive the premutation size, some will receive the full mutation size (more than 200 CGG repeats). Premutation mother to son The sons also have a 50 percent chance of inheriting the stable version of the FMR1 gene from a premutation female. As noted above, this does not guarantee that if the first son receives the premutation, the second will receive the stable version. For each son, there is an equal probability of receiving either of the X chromosomes from the mother. A premutation female with two sons could have zero, one or two sons with the stable version. The major group of individuals impacted by fragile X syndrome are sons who receive the X chromosome with the premutation from their mothers. The males who inherit the X chromosome with the premutation from their mothers, are more likely than their sisters to have an expansion to the full mutation. The probability that a son will get the full mutation depends on the number of repeats that the mother has. If she is at the low end of the premutation range (56-70), she is less likely to have a son with the full mutation than if she is at the high end of the premutation range (more than 100 repeats). Full mutation mother to daughters and sons The children of a female with a full mutation on one chromosome and a stable version on the other, each have a 50 percent chance of receiving the stable version and a 50 percent chance of receiving the mutant version. Most of those who receive the mutation will have the full mutation although there have been cases observed in which the number of repeats was reduced. Summary Individuals with the full mutation for fragile X syndrome are the result of a series of events. A rare individual with the stable version has a child with the premutation. That child passes the premutation to some of the offspring. Over several generations the number of repeats increases. At some point, a female with a large premutation has a child in which the number of repeats has increased to more than 200 and that full mutation results in fragile X syndrome.
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© copyright 1998-2008 NFXF |
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A male has an X chromosome and a Y chromosome. If he passes on the Y
chromosome to a child, the child will be a male. Since the FMR1 gene is on the X chromosome, the father cannot pass on any version of the FMR1 gene to his sons.
Females have two X chromosomes. Each child has a random chance of receiving
one or the other of these two X chromosomes. A female who has one copy of the premutation and one copy of the stable version can pass either the premutation or
the stable version to her daughters. Every daughter has an equal probability of receiving one or the other version.
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