Molecular genetics of inherited diseases involving human chromosome 4.

Two molecular genetic strategies have widely been employed to characterize candidate genes for human inherited diseases; identification of disease genes via positional cloning and characterization of altered candidate genes in affected persons. Both approaches allowed to uncover disease genes. A well-known example for positional cloning is the identification of the Huntington's disease (HD) gene on human chromosome 4. In other diseases such as piebaldism, Hurler/Scheie syndrome and a form of autosomal recessive retinitis pigmentosa, the disease gene has first been analyzed and later been localized to human chromosome 4. Steady progress in the human genome project permits to combine affected families pointing to the chromosomal localization of the disease causing defects. Then the genes are investigated that are already mapped to this particular region. Accordingly the achondrodysplasia gene has been identified within six months after its chromosomal localization. In order to evaluate cloned genes as potential candidates for disorders linked to chromosome 4, it is important to assign all genes to chromosomal (sub)regions. Furthermore in excess of 140 closely spaced microsatellites on chromosome 4 as well as many "expressed sequence tags" will help to narrow in on additional disease genes.