Deletion of 150 kb in the minimal DiGeorge/velocardiofacial syndrome critical region in mouse

Deletions or rearrangements of human chromosome 22q11 lead to a variety of related clinical syndromes such as DiGeorge syndrome (DGS) and velocardiofa cial syndrome (VCFS), In addition, patients with 22q11 deletions have an in creased incidence of schizophrenia and several studies have mapped suscepti bility loci for schizophrenia to this region. Human molecular genetic studi es have so far failed to identify the crucial genes or disruption mechanism s that result in these disorders. We have used gene targeting in the mouse to delete a defined region within the conserved DGS critical region (DGCR) on mouse chromosome 16 to prospectively investigate the role of the mouse D GCR in 22q11 syndromes. The deletion spans a conserved portion (similar to 150 kb) of the proximal region of the DGCR, containing at least seven genes (Znf741, Idd, Tsk1, Tsk2, Es2, Gscl and Ctp), Mice heterozygous for this d eletion display no findings of DGS/VCFS in either inbred or mixed backgroun ds. However, heterozygous mice display an increase in prepulse inhibition o f the startle response, a manifestation of sensorimotor gating that is redu ced in humans with schizophrenia, Homozygous deleted mice die soon after im plantation, demonstrating that the deleted region contains genes essential for early post-implantation embryonic development, These results suggest th at heterozygous deletion of this portion of the DGCR is sufficient for sens orimotor gating abnormalities, but not sufficient to produce the common fea tures of DGS/VCFS in the mouse.