A moderate degree of mental retardation (IQs around 50) found in males carrying an X chromosome that has a fragile site at the interface of bands q27 and q28. The frequency of such hemizygotes is about 1.8 per 1,000. X-linked mental retardation accounts for about 25% of all mentally retarded males. The fragile X site contains a gene that is expressed in human brain cells. The gene designated FMR-1 (fragile X mental retardation 1) generates a 4.8-kilobase mRNA, which encodes a protein containing 657 amino acids. Upstream of the coding region of the gene is a segment in which the CGG triplet is repeated about 30 times. In cases where the CGG repeat is expanded 50–200 times, the cytologically detectable fragile X phenotype appears. Males with this XF show normal intelligence, but are transmitters. F1 daughters who receive this XF also have normal intelligence; however, the expansion of the CGG repeat is activated in the XF once it is transmitted to the next generation. Since the expansion occurs during early development, the F2 children are genetic mosaics. Their germ cells contain maternal XFs with 50–200 repeats, but cells in other tissues may have thousands of repeats. The FMR-1 gene is evidently inactivated under such circumstances, and mental development is impaired. Some 30% of the females and 50% of the males in this F2 generation are retarded. See Chronology, 1969, Lubs; 1991, Verkerk et al.; CpG island, DNA methylation, fragile chromosome site, parental imprinting, trinucleotide repeats.
Subjects: Genetics and Genomics.