X chromosome imprinting in fragile X syndrome.

Laird et al. (1987) hypothesized that there are at least four cis-acting alleles or 'chromosome states' at Xq27 that increasingly delay replication at this chromosomal area resulting in its increasing fragility in vitro. When on the inactive X chromosome, the proposed third ('mutated') allele can permanently block reactivation of its cis Xq27 area as the chromosome passes through female meiosis. Males and some females who inherit such an 'imprinted' fragile X chromosome (the fourth proposed allele) will be clinically affected due to impaired transcription of genes in the 'imprinted' Xq27 area. To test this hypothesis, late replication reverse banding patterns at Xq27 were evaluated in cultured lymphoblastoid cell lines from 25 subjects. Our data suggest that DNA replication of the presumed 'imprinted' Xq27 region in affected fragile X patients is indeed later relative to Xq27 on the active X chromosome in other subjects. These results support in part Laird's hypothesis of chromosomal imprinting in fragile X syndrome.