Mice overexpressing genes from the 22q11 region deleted in velo-cardio-facial syndrome/DiGeorge syndrome have middle and inner ear defects

Velo-cardio-facial syndrome/DiGeorge syndrome (VCFS/DGS) is a congenital an omaly disorder associated with hemizygous 22q11 deletions. We previously sh owed that bacterial artificial chromosome (BAC) transgenic mice overexpress ing four transgenes, PNUTL1, (CDCrel-1), GP1B beta, TBX1 and WDR14, had red uced viability, cardiovascular malformations and thymus gland hypoplasia. S ince these are hallmark features of VCFS/DGS, we analyzed the mice for addi tional anomalies. We found that the mice have important defects in the midd le and inner ear that are directly relevant to the disorder. The most strik ing defect was the presence of chronic otitis media, a common finding in VC FS/DGS patients. In addition, the mice had a hyperactive circling behavior and sensorineural hearing loss. This was associated with middle and inner e ar malformations, analogous to Mondini dysplasia in humans reported to occu r in VCFS/DGS patients. We propose that overexpression of one or more of th e transgenes is responsible for the etiology of the ear defects in the mice . Based upon its pattern of expression in the ear and functional studies of the gene, TbX1 likely plays a central role. Haploinsufficiency of TBX1 may be responsible for ear disorders in VCFS/DGS patients.