Behavior of mice with mutations in the conserved region deleted in velocardiofacial/DiGeorge syndrome.
Velocardiofacial/DiGeorge syndrome (VCFS/DGS) is a developmental disorder caused by a 1.5 to 3-Mb hemizygous 22q11.2 deletion. VCFS/DGS patients display malformations in multiple systems, as well as an increased frequency of neuropsychiatric defects including schizophrenia. Haploinsufficiency of TBX1 appears to be responsible for these physical malformations in humans and mice, but the genes responsible for the neuropsychiatric defects are unknown. In this study, two mouse models of VCFS/DGS, a deletion mouse model (Lgdel/+) and a single gene model (Tbx1 +/-), as well as a third mouse mutant (Gscl -/-) for a gene within the Lgdel deletion, were tested in a large behavioral battery designed to assess gross physical features, sensorimotor reflexes, motor activity nociception, acoustic startle, sensorimotor gating, and learning and memory. Lgdel/+ mice contain a 1.5-Mb hemizygous deletion of 27 genes in the orthologous region on MMU 16 and present with impairment in sensorimotor gating, grip strength, and nociception. Tbx1 +/- mice were impaired in grip strength similar to Lgdel/+ mice and movement initiation. Gscl -/- mice were not impaired in any of the administered tests, suggesting that redundant function of other Gsc family members may compensate for the loss of Gscl. Thus, although deletion of the genes in the Lgdel region in mice may recapitulate some of the behavioral phenotypes seen in humans with VCFS/DGS, these phenotypes are not found in mice with complete loss of Gscl or in mice with heterozygous loss of Tbx1, suggesting that the neuropsychiatric and physical malformations of VCFS/DGS may act by different genetic mechanisms.
Long
Jeffrey M
JM
Department of Medicine, University of California, San Diego School of Medicine, La Jolla, CA 92093-0627, USA.
LaPorte
Patricia
P
Merscher
Sandra
S
Funke
Birgit
B
Saint-Jore
Bruno
B
Puech
Anne
A
Kucherlapati
Raju
R
Morrow
Bernice E
BE
Skoultchi
Arthur I
AI
Wynshaw-Boris
Anthony
A
D000015:Abnormalities, Multiple / Q000235:genetics* / Q000503:physiopathology*; D000818:Animals; D001522:Behavior, Animal; D003213:Conditioning, Psychological; D017124:Conserved Sequence; D004062:DiGeorge Syndrome / Q000235:genetics* / Q000503:physiopathology*; D004195:Disease Models, Animal; D005106:Exploratory Behavior; D005260:Female; D017353:Gene Deletion; D018476:Hypokinesia / Q000235:genetics / Q000503:physiopathology; D008297:Male; D008568:Memory; D051379:Mice; D008817:Mice, Mutant Strains; D009043:Motor Activity; D009046:Motor Neurons; D018908:Muscle Weakness / Q000235:genetics / Q000503:physiopathology; D009475:Neurons, Afferent; D009619:Nociceptors; D013216:Reflex, Startle