This proposal requests support for a 5 year continuation of the Banbury Conferences on Fragile X syndrome (FXS). Including an initial conference, six such meetings have been held at Banbury Conference Center at Cold Spring Harbor Laboratory on Long Island NY. We propose a series of five annual interdisciplinary conferences on basic and clinical research relevant to fragile X syndrome (FXS). The conferences are intended to bring together a broad range of scientists, both those working on FXS and others in allied, relevant fields. Another goal is to introduce young scientists, including females and minorities, to the area. Fragile X syndrome is the most common inherited cause of mental retardation. It arises due to expansion of an unstable region of trinucleotide repeats in the 5' untranslated promoter region of the FMR-1 gene, causing hypermethylation of cytosine residues and, generally, silencing of the gene. A number of mouse FMR-1 knockout models for the syndrome have or are about to become available. The function of the fragile X mental retardation protein (FMRP) is believed to be the transport and translational regulation of a subset of mRNAs with a diverse set of cellular functions. FMRP appears to be translated at synapses in response to activation of metabotropic glutamate receptors. Relatively subtle phenotypic effects of the disorder are seen in the gross size of several brain regions and in the fine structure of synapses in humans and in the knockout mouse model. As the Banbury Conferences have made clear (summarized in Sec. C), advances in our knowledge of this disorder are occurring very rapidly. There is no other meeting devoted exclusively to basic and clinical research on FXS, and the participants consistently report the Banbury Conference to be extremely valuable. ? ?