The long term objective of this proposal is the characterization at the molecular level of the causes of the developmental defects associated with Langer-Giedion syndrome and the related syndromes trichorhinophalangeal syndrome type I (TRPS-I) and hereditary multiple exostoses. These three dysmorphology syndromes most probably represent different phenotypic expressions of a single """"""""contiguous gene syndrome"""""""" resulting from lesions in a region near the distal end of the long arm of human chromosome 8. Langer-Giedion syndrome results from chromosomal deletions or other rearrangements affecting both the gene responsible for the dysmorphic features of TRPS-I and the gene responsible for producing exostoses.
The specific aims of this proposal are directed at identifying and characterizing the genes from this region. To this end, cell lines, including somatic cell hybrids, will be established from patients with Langer-Giedion syndrome and TRPS-I. The endpoints of the deletions and rearrangements of patients' chromosomes will be mapped at high resolution on an overlapping clone map of the Langer-Giedion region. This will help to narrow down the critical segment of the chromosome responsible for these syndromes. Linkage analysis of families segregating the TRPS-I and exostoses genes will be used to map the locations of recombination events that may further narrow the regions containing these genes. Expressed sequences within the regions identified by these methods will be identified by screening cDNA libraries, hybridizing genomic clones to Northern blots, searching for evolutionarily conserved sequences, and screening for functional splice sites which mark the boundaries of exons. The genes identified in this way will be characterized at the nucleotide sequence level, and their possible roles in the etiology of Langer-Giedion syndrome will be explored by screening for mutations in patients. The information obtained in this study will increase our understanding of normal developmental processes as well as the disease process, and is likely to lead to improved treatments for patients affected with these syndromes.
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