The fragile X mutation

Abstract Fragile X syndrome, the most common cause of inherited mental retardation, is the result of unstable expansions of a CGG repeat located in the 5′ untranslated region of the FMR1 gene. Normal alleles consist of 6‐50 CGG repeats, in general interspersed by 1–3 AGGs. Moderate expansions up to 200 repeats, called premutations, are found in phenotypically normal carrier males or females. When transmitted by a female, a premutation has a risk of up to 100% of further expansion to an abnormally methylated full mutation (230 to >1,000 CGGs), which results in shut‐down of FMR1 expression. In contrast, affected males with a full mutation carry a premutation in their sperm that is transmitted to their daughters. On maternal transmission, the timing of the transition from premutation to full mutation remains unsolved. It is generally believed, but has not been proven that this is a postzygotic event, in which case an imprinting mechanism is required to distinguish a premutation carried on a maternal or paternal X chromosome. As in other trinucleotide expansion diseases, linkage disequilibrium between the fragile X mutations and haplotypes of adjacent polymorphisms has been found in various populations, indicating founder effects. These studies have suggested that normal alleles that carry long perfect CGG repeats may constitute alleles that are predisposed to multistep expansion over many generations. The ability to detect the various types of mutations has revolutionized the diagnosis of the disease and genetic counseling, and should allow more precise estimates of the population frequency of the fragile X syndrome. It may also allow screening for carrier females in the general population. We discuss possible mechanisms of expansion in light of the unusual structural properties proposed for CGG repeats. Various other folate‐sensitive fragile sites that are also caused by unstable expansions of CGG (CCG) repeats are being cloned and characterized. In particular, methylated expansions at the FRAXE locus appear to be associated with mild mental retardation. © 1995 Wiley‐Liss, Inc.