Huntington disease (HD) is a severe autosomal dominant neurodegenerative disorder associated with a novel gene (IT15). Recently, we reported the cloning of Hdh, the murine homologue of IT 15. Here, using an interspecific backcross, we have mapped both Hdh and the mouse homologue of human α-adducin (Add1), a membrane-associated cytoskeletal protein gene. Both of these genes map in the same position on mouse chromosome 5 in a region associated with ancestral chromosomal rearrangements and show no recombination with D5H4S43, D5H4S115, and D5H4S62, the murine homologues of D4S43, D4S115, and D4S62, respectively. Further mapping studies of humans, mice, and other mammalian species should reveal the nature of the rearrangements affecting this chromosomal segment during mammalian evolution. © 1994 Academic Press Inc.