This program is designed to provide facilities and resources for human genetic mapping in Johns Hopkins University, to develop 2 technical approaches to mapping, and to conduct mapping studies of specific skeletal, neurologic, and ophthalmologic disorders and of a developmental regulatory gene locus. A facility for establishing lymphoblastoid cell lines, preparing DNA, and banking both will also serve as a repository for probes and restriction enzymes and will provide the service of gene localization by in situ hybridization and hybridization to DNAs from panels of somatic cell hybrids. The Lancaster County Amish, in whom studies have been going on by members of this department for over 25 years, will be further developed as a resource for family linkage studies. Facilities for genetic data management and analysis, particularly of family linkage data, will be developed. Technical projects will be concerned with cloning large DNA segments in yeast artificial chromosomes (YAC) and will provide a new method for detecting polymorphism based on polymerase chain reaction. By genetic and physical approaches, interference to crossingover in the pericentromeric regions will be evaluated quantitatively. A locus that controls the level of hemoglobin F, called FCP (F-cell production), appears to be on Xq. This locus will be mapped and cloning will be attempted. Multiple exostoses (and the trichorhinophalangeal syndrome), which may be on chromosome 8, will be investigated by family linkage methods. The related Langer- Giedion syndrome will be investigated by cloning of the deleted portion of 8q24. The nail-patella syndrome, which is located in 9q34 very close to adenylate kinase-1 and moderately close to ABO, will be studied by candidate gene and cloning approaches. By family linkage studies, the map location of 2 skeletal dysplasias of unknown biochemical cause, Ellis-van Creveld syndrome and cartilage-hair hypoplasia, will be determined as the first step toward to defining basic pathogenesis. Mapping of three neurologic disorders - - Charcot-Marie-Tooth disease (CMT), Gilles de la Tourette syndrome (GTS) and Werdnig-Hoffman (WH) disease -- will be studied by the family linkage approach (first 2) and by homozygosity mapping in offspring of consanguineous parents (the last). The gene that is mutant in Norrie disease will be sought by cloning experiments in case(s) of deletion of Xp11. The core facilities will assist other mapping studies by the members of the departments of psychiatry, ophthalmology, and neurology. The facilities will also make it possible for rapid mapping of the mRNAs being isolated in several laboratories as contributions to the cDNA map of the human genome.

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National Institute of General Medical Sciences (NIGMS)
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