While the location of this fragile site established that fragile X syndrome was indeed X-linked, inheritance of this disorder was clearly not typical of other X-linked disorders. At first, it was believed that fragile X syndrome was an X-linked recessive genetic disorder. However, there were many observations inconsistent with this inheritance pattern.
If the disorder was truly inherited in an X-linked recessive manner, heterozygote carrier women would not display any characteristics of the syndrome, and all carrier males would. But there were reports of affected females, and of males who carried the fragile site but were unaffected. It was particularly difficult to reconcile that some male carriers could be so severely affected while others were completely unaffected.
Because of these puzzling observations, in 1985 Stephanie Sherman and her colleagues studied the inheritance pattern of fragile X syndrome more closely. They demonstrated that the risk of expressing mental retardation was dependent on the individual's position in the pedigree, with risk increasing in later generations. The daughter of an unaffected male carrier was more likely to have affected offspring than the mother of the unaffected male carrier was: something had changed on the X chromosome over the two generations. This observation became known as the "Sherman paradox" and was crucial to understanding the genetic mutation that causes fragile X syndrome.
To explain the unusual inheritance pattern, Sherman, her colleagues, and several other scientists hypothesized that the alleged gene for fragile X syndrome was mutated in a two-step process. They proposed that the first mutation caused a "premutation" state that produced no clinical symptoms, and that a second mutation was required to convert the premutation to a "full mutation" form that was associated with the characteristic symptoms
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