Human Molecular Genetics, Vol 8, 2229-2237, Copyright © 1999 by Oxford University Press
WL Kimber, P Hsieh, S Hirotsune, L Yuva-Paylor, HF Sutherland, A Chen, P Ruiz- Lozano, SL Hoogstraten-Miller, KR Chien, R Paylor, PJ Scambler and A Wynshaw- Boris
Deletions or rearrangements of human chromosome 22q11 lead to a variety of
related clinical syndromes such as DiGeorge syndrome (DGS) and velo--
cardiofacial syndrome (VCFS). In addition, patients with 22q11 deletions
have an increased incidence of schizophrenia and several studies have
mapped susceptibility loci for schizophrenia to this region. Human
molecular genetic studies have so far failed to identify the crucial genes
or disruption mechanisms 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 DGCR in 22q11 syndromes. The deletion spans a
conserved portion (~150 kb) of the proximal region of the DGCR, containing
at least seven genes ( Znf74l, Idd, Tsk1, Tsk2, Es2, Gscl and Ctp ). Mice
heterozygous for this deletion display no findings of DGS/VCFS in either
inbred or mixed backgrounds. However, heterozygous mice display an increase
in prepulse inhibition of the startle response, a manifestation of
sensorimotor gating that is reduced in humans with schizophrenia.
Homozygous deleted mice die soon after implantation, demonstrating that the
deleted region contains genes essential for early post-implantation
embryonic development. These results suggest that heterozygous deletion of
this portion of the DGCR is sufficient for sensorimotor gating
abnormalities, but not sufficient to produce the common features of
DGS/VCFS in the mouse.
ARTICLES
Deletion of 150 kb in the minimal DiGeorge/velocardiofacial syndrome critical region in mouse
Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA,
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