Fragile X syndrome: a hypothesis regarding the molecular mechanism of the phenotype

Among all the human chromosomal fragile sites currently recognized, the fragile site mapping to Xq27.3 is the only one associated with an abnormal phenotype. This phenotype, referred to as the Martin-Bell or fragile X syndrome, has mental retardation as its most important manifestation. We propose that this site is associated with an abnormal phenotype due its location on the X chromosome, particularly it's proximity to the q telomere. Thus, if an in vivo break should occur with loss of Xq28 in the fra(X) male, the cell would be nullisomic for the genes distal to the fragile site. Similarly, a female cell would be functionally nullisomic if the break occurred on the active X. Breakage and loss of genetic material at other fragile sites either would have no impact due to complementation by homologous genes or would be lethal if X-linked with a significant deletion (i.e. fra(Xq22]. This leads to the proposal that the fragile X syndrome is due to mosaic nullisomy of distal genes. We describe below the implications of this model and a means to test this hypothesis.