Proposed Mechanism of Inheritance and Expression of the Human Fragile-X Syndrome of Mental Retardation

Charles D. Laird ¹

¹ Departments of Zoology and Genetics, University of Washington NJ-15, Seattle, Washington 98195

A mechanism is proposed for the inheritance and expression of the fragile-X-linked syndrome of mental retardation in humans. Two independent events are required for expression of the syndrome: the fragile- X mutation, and X chromosome inactivation in pre-oogonial cells. The fragile-X mutation at site Xq27 has little or no effect until the chromosome is inactivated in a female as part of the process of dosage compensation. At a stage where the inactivated X chromosome would normally be reactivated in preparation for oogenesis, the mutation results in a local block to the reactivation process. This block to reactivation leads to mental retardation in progeny by reducing the level of products from the unreactivated Xq27 region in male cells, and, for a heterozygous female, in somatic cells in which the normal X chromosome has been inactivated. Published data relevant to this proposed mechanism are discussed.

This article has been cited by other articles:

				C. D. Laird, N. D. Pleasant, A. D. Clark, J. L. Sneeden, K. M. A. Hassan, N. C. Manley, J. C. Vary Jr., T. Morgan, R. S. Hansen, and R. Stoger From The Cover: Hairpin-bisulfite PCR: Assessing epigenetic methylation patterns on complementary strands of individual DNA molecules PNAS, January 6, 2004; 101(1): 204 - 209. [Abstract] [Full Text] [PDF]

				V. K. Lloyd, D. A. Sinclair, and T. A. Grigliatti Genomic Imprinting and Position-Effect Variegation in Drosophila melanogaster Genetics, April 1, 1999; 151(4): 1503 - 1516. [Abstract] [Full Text]

				M. K. Raghuraman, B. J. Brewer, and W. L. Fangman Cell Cycle-Dependent Establishment of a Late Replication Program Science, May 2, 1997; 276(5313): 806 - 809. [Abstract] [Full Text]

				J R Chaillet, D S Bader, and P Leder Regulation of genomic imprinting by gametic and embryonic processes. Genes & Dev., May 15, 1995; 9(10): 1177 - 1187. [Abstract] [PDF]

				J. Nancarrow, E Kremer, K Holman, H Eyre, N. Doggett, D Le Paslier, D. Callen, G. Sutherland, and R. Richards Implications of FRA16A structure for the mechanism of chromosomal fragile site genesis Science, June 24, 1994; 264(5167): 1938 - 1941. [Abstract] [PDF]

				D Heitz, F Rousseau, D Devys, S Saccone, H Abderrahim, D Le Paslier, D Cohen, A Vincent, D Toniolo, G Della Valle, et al. Isolation of sequences that span the fragile X and identification of a fragile X-related CpG island Science, March 8, 1991; 251(4998): 1236 - 1239. [Abstract] [PDF]

				M Monk Genomic imprinting. Genes & Dev., August 1, 1988; 2(8): 921 - 925. [PDF]