The molecular basis of genetic disease

The pace of localization and characterization of genes affected in human genetic disorders is quickening. Many important genes were localized or characterized recently: genes for in cystic fibrosis, NF-2, Marfan's syndrome and xeroderma pigmentosum, to name a few. Also, in the past 15 months, the CFTR gene affected in cystic fibrosis has been isolated, the first disease gene to be isolated without use of previous cytogenetic clues, such as deletions or translocations in sporadic cases. Other examples should follow, although we have been disappointed to date by the difficulties encountered in the isolation of Huntington's disease gene which was localized a number of years ago to distal chromosome 4p. It is still very difficult to isolate a disease gene without critical cytogenetic information. New improved techniques for finding the desired expressed sequences in a large cloned segment of human DNA are needed. Our ability to find mutant alleles of a given sequence has expanded greatly with the recent technical advances in denaturing gradient gel electrophoresis, chemical cleavage, and single-stranded conformational electrophoresis. One would predict that information derived from the human genome project will have a major impact upon the isolation of further disease genes. As whole regions of human chromosomes or indeed entire chromosomes are physically mapped and cloned as continuous, overlapping YACs (yeast artificial chromosomes), isolation of disease genes will become easier and easier.(ABSTRACT TRUNCATED AT 250 WORDS)