Disorganization in mice and humans

Disorganization (Ds) is an autosomal dominant mouse mutant that produces a remarkable array of birth defects. So variable is the phenotype that no two mice appear identical. Ds also has markedly reduced penetrance, with 85-99 % of Ds mice having no apparent anomalies. Paired structures are often affe cted, but always asymmetrically. Although the Ds gene has yet to be identif ied, it is thought that Ds is a gain-of-function mutation, and that Ds malf ormations are thought to arise through a two-hit mechanism. Unlike the two- hit model that has been used to describe the development of retinoblastoma, the "second hit" for Ds is thought not to arise in the other Ds allele, Al though there is a long list of anomalies seen in Ds mice, two stand out as most characteristic: hamartomatous skin papillae, and mirror-image limb dup lications. Through the observation of these unusual anomalies in human case s, the possibility of a human homologue of Ds was suggested. However, in re viewing types of anomalies seen in Ds mice, it is apparent that cases with these unusual defects represent only one end of the spectrum of the Ds phen otype. Ds may be the genetic basis for more usual and seemingly sporadic hu man birth defects as well. (C) 2001 Wiley-Liss, Inc.