The human globin genes have provided an excellent model for the investigation of genetic disease at the molecular level. Through the application of recombinant DNA methods the precise genetic bases of several different forms of inherited disorders of hemoglobin synthesis (the thalassemias) have been defined. These defects involve DNA sequences influencing gene transcription and RNA processing as well as mRNA function. Furthermore, a potentially general method has been developed for the dissection of a disease by combining restriction polymorphism analysis with study of cloned genes. The focus of this research proposal is to (1) extend the systematic analysis of Beta-thalassemia to several different ethnic groups in order to more completely defined the existing mutations, (2) evaluate the applicability of the use of chromosome haplotypes to define different mutant alleles by investigation of these ethnic groups, (3) examine the mechanism by which nucleotide substitutions in the upstream flanking region adversely affect gene transcription, (4) systematically analyze the transient expression of normal and mutant Beta-globin genes in erythroid cell lines in an effort to identify cell specific enhancer functions, RNAS processing, or meataboism, and (5) use the available and future date on thalassemia mutations and chromosome haplotypes to ascertain the origin of various point mutations. These studies should serve to nearly complete the molecular analysis of the Beta-thalassemias and will materially assist in establishing prenatal diagnostic tests for prevalent alleles in various populations at risk. The lessons of the human globin system may be useful in the near future in consideration of other disorders of single-copy loci in man.
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