PROPOSED GENETIC-BASIS OF HUNTINGTONS-DISEASE

I propose that Huntington's disease (HD) is caused by dominant position-effect variegation, a phenomenon for which new information is available in Drosophila melanogaster: The essential features of this proposal are that (1) the HD mutation is the result of a chromosome alteration that inactivates transcription of a nearby structural gene or genes (cis-inactivation); the combination of this proposed chromosome alteration and the structural gene(s) is termed the HD allele; (2) there is pairing in some somatic cells between the HD and HD+ alleles on homologous chromosomes; (3) as a result of this somatic pairing, the HD mutation also inactivates transcription of the HD+ structural gene on the normal homologue (trans-inactivation), resulting in complete dominance of the mutation; (4) polymorphism for an X-linked recessive modifier of position-effect variegation means that the age of onset of symptoms of HD will depend on which parent the HD mutation was inherited from. The fully dominant nature of HD and the parental-source effect on the age of onset are thus both understandable within the genetic and epigenetic paradigm of position-effect variegation. © 1990.