Mouse models for the Wolf-Hirschhorn deletion syndrome

Wolf-Hirschhorn syndrome (WHS) is a deletion syndrome caused by segmental h aploidy of chromosome 4p16.3, Its hallmark features include a 'Greek warrio r helmet' facial appearance, mental retardation, various midline defects an d seizures. The WHS critical region (WHSCR) lies between the Huntington's d isease gene, HD, and FGFR3, in mice, the homologs of these genes map to chr omosome 5 in a region of conserved synteny with human 4p16.3, To derive mou se models of WHS and map genes responsible for subphenotypes of the syndrom e, five mouse lines bearing radiation-induced deletions spanning the WHSCR syntenic region were generated and characterized. Similar to WHS patients, these animals were growth-retarded, were susceptible to seizures and showed midline (palate closure, tail kinks), craniofacial and ocular anomalies (c olobomas, corneal opacities). Other phenotypes included cerebellar hypoplas ia and a shortened cerebral cortex. Expression of WHS-like traits was varia ble and influenced by strain background and deletion size, These mice repre sent the first animal models for WHS, This collection of nested chromosomal deletions will be useful for mapping and identifying loci responsible for the various subphenotypes of WHS, and provides a paradigm for the dissectio n of other deletion syndromes using the mouse.