Mental retardation (MR) is a common developmental disability affecting about 2-3% of the human population. The causation in at least half of all MR cases is still unknown. It is expected that the genetic component of MR, in part, is due to alterations in molecular pathways involved in cognitive function and that defining the genes involved will help in defining brain functions important for intellectual and adaptive abilities. Our approach is based on the assumption that the genetic component of MR is caused by mutations in a large number of genes distributed throughout the genome. The characterization of disease-associated translocation breakpoints has proven to be a productive strategy to identify the genes responsible for specific disorders. The immediate goal of the study is to utilize de novo balanced chromosomal translocations to identify, clone, and characterize 4-5 autosomal genes involved in brain development and function, which, when defective, cause MR. The long-term goals of our research are 1) to aid in the understanding of genes and genetic pathways involved in brain development and function that play a role in cognitive abilities, and 2) to improve diagnosis, and ultimately, develop treatment strategies for mental retardation. In the initial grant period, 11 patients with MR and balanced chromosomal translocations have been characterized. Ten potential MR loci have been finely mapped to discrete regions of the autosomes. We have initiated a positional cloning strategy that involves identifying genes disrupted or altered in these patients and confirming the MR association by looking for mutations in a large cohort of patients, both female (>600) and male (>600), with idiopathic MR. The approach has been used successfully in cloning one X-linked MR gene and in determining the prevalence of mutations of the gene among male patients with MR. This strategy, including maximal utilization of new human genome sequence data, will continue to be utilized to identify and characterize three to four autosomal MR genes over the next five years.
The Specific Aims of this proposed research are 1) identify and isolate the candidate MR genes associated with the translocation breakpoints; 2) determine and establish the identity of each of the isolated MR genes; 3) delineate additional potential autosomal MR loci in 4 patients with balanced translocations and MR enrolled during initial grant period. Identification and characterization of the genes involved should be a major advance in the understanding of brain functions critical for the development of intellectual and adaptive abilities as well as facilitating objective diagnosis in some cases of MR.
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