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 affected, but always asymmetrically. Although the Ds gene has yet to be identified, it is thought that Ds is a gain-of-function mutation, and that Ds malformations 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. Although there is a long list of anomalies seen in Ds mice, two stand out as most characteristic: hamartomatous skin papillae, and mirror-image limb duplications. Through the observation of these unusual anomalies in human cases, the possibility of a human homologue of Ds was suggested. However, in reviewing 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 phenotype. Ds may be the genetic basis for more usual and seemingly sporadic human birth defects as well.