Heterozygous chromosomal deletions within 22q11.2 are the most frequent cause of DiGeorge syndrome, velocardiofacial syndrome and conotruncal anomaly face syndrome, collectively referred to as De122q11 syndrome. The De122q11 syndrome phenotype has key components that are thought to derive from abnormal development of the pharyngeal arch system, namely, cardiovascular, thyrnic, parathyroid and craniofacial abnormalities. However, in addition, del22q11 syndrome patients have behavioral and neuropsychiatric problems, which are a major challenge to the clinical management of these patients, second only to their cardiovascular disease. The developmental origins of the behavioral and neuropsychiatric disorders are unknown. Here we show that, similarly to human patients, mice that model Del22q11 syndrome (Dfl/+ mice) have schizophrenia-related behavior and learning and memory impairments. This suggests that a gene/s that modulates these behaviors lies within the genomic regions deleted in patients and in DflI+ mice. The main purpose of this proposal is to identify and isolate gene/s responsible for the mouse behavioral phenotype. Specifically, we propose to use a panel of mouse mutants that we have generated, which carry deletions that are smaller than, and partially overlapping with, Dfl, in order to localize the behavioral phenotypes to one or more small genomic regions that will be amenable to functional rescue. We will then mutate single candidate genes using homologous recombination for validation and initiate a functional analysis. Our preliminary data, and the unique resources available to this project, provide the first concrete opportunity to identify behavioral genes relevant to this relatively common genetic syndrome.
| Pascoe, Sophie J S; Hargreaves, James R; Langhaug, Lisa F et al. (2013) 'How poor are you?' -- a comparison of four questionnaire delivery modes for assessing socio-economic position in rural zimbabwe. PLoS One 8:e74977 |
