The study of genetic disorders contributing to the understanding of gene functioning

Abstract

The Human Genome Project is supposed to finish, at the beginning of the next millennium, the sequencing and characterization of the 100 to 150.000 human genes responsible for our normal and pathological traits. The ultimate goal of this project is to understand how our genes work, how they interact among them as well as with the environment. The study of human disorders at the molecular level has brought tremendous contributions to the identification and comprehension of various molecular mechanisms such as, for example: dynamic genes, alternative splicing generating different products from the same gene, genomic imprinting. Besides that, molecular analysis is showing for a growing number of disorders that different clinical entities may result from mutations in the same gene (such as for example the craniosynostosis Apert, Pfeiffer and Crouzon) , or from duplication or deletion in the same gene (such as in the neuropathies Charcot-Marie-Tooth or CMT and hereditary neuropathy with pressure palsies liability or HNPP). On the other hand, for other conditions , it has been demonstrated that several genes may lead to the same phenotype. In some cases, such as for limb-girdle muscular dystrophies , each gene may act separately (non-allelic genetic heterogeneity) or together to produce a specific phenotype such as in psychiatric disorders (in multifactorial inheritance ) . After the identification of a disease-gene , the next step is to understand what is the mechanism leading to a genetic disorder. For example, it may occur due to a reduced amount of the gene product (haplo insufficiency) such as for example in the syndrome of Treacher Collins, to a dominant negative effect (such as in Marfan s syndrome) or a gain of function (such as in spinocerebelar ataxias or Charcot-Marie disease. All these molecular mechanisms are extremely complex and with rare exceptions little is understood for genetic disorders despite the great advances of the last decade. For example, the great intra and interfamilial variability observed among patients carrying the same pathological mutations is difficult to be explained... (AU)