title: Mice overexpressing genes from the 22q11 region deleted in velo-cardio-facial syndrome/DiGeorge syndrome have middle and inner ear defects.
abstract: Velo-cardio-facial syndrome/DiGeorge syndrome (VCFS/DGS) is a congenital anomaly disorder associated with hemizygous 22q11 deletions. We previously showed that bacterial artificial chromosome (BAC) transgenic mice overexpressing four transgenes, PNUTL1, (CDCrel-1), GP1B beta, TBX1 and WDR14, had reduced viability, cardiovascular malformations and thymus gland hypoplasia. Since these are hallmark features of VCFS/DGS, we analyzed the mice for additional anomalies. We found that the mice have important defects in the middle and inner ear that are directly relevant to the disorder. The most striking defect was the presence of chronic otitis media, a common finding in VCFS/DGS patients. In addition, the mice had a hyperactive circling behavior and sensorineural hearing loss. This was associated with middle and inner ear malformations, analogous to Mondini dysplasia in humans reported to occur in VCFS/DGS patients. We propose that overexpression of one or more of the 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.
authors.affiliation: Department of Molecular Genetics, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA.
authors.forename: B
authors.initials: B
authors.lastname: Funke
authors.forename: J A
authors.initials: JA
authors.lastname: Epstein
authors.forename: L K
authors.initials: LK
authors.lastname: Kochilas
authors.forename: M M
authors.initials: MM
authors.lastname: Lu
authors.forename: R K
authors.initials: RK
authors.lastname: Pandita
authors.forename: J
authors.initials: J
authors.lastname: Liao
authors.forename: R
authors.initials: R
authors.lastname: Bauerndistel
authors.forename: T
authors.initials: T
authors.lastname: Schüler
authors.forename: H
authors.initials: H
authors.lastname: Schorle
authors.forename: M C
authors.initials: MC
authors.lastname: Brown
authors.forename: J
authors.initials: J
authors.lastname: Adams
authors.forename: B E
authors.initials: BE
authors.lastname: Morrow
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics* / Q000473:pathology; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D018797:Cell Cycle Proteins; D002872:Chromosome Deletion; D002892:Chromosomes, Human, Pair 22 / Q000235:genetics*; D004062:DiGeorge Syndrome / Q000235:genetics* / Q000473:pathology; D004427:Ear Diseases / Q000235:genetics / Q000473:pathology; D007758:Ear, Inner / Q000473:pathology*; D004432:Ear, Middle / Q000473:pathology*; D004622:Embryo, Mammalian / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D006319:Hearing Loss, Sensorineural / Q000235:genetics / Q000473:pathology; D006801:Humans; D017403:In Situ Hybridization; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics; D010641:Phenotype; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000235:genetics; D011506:Proteins / Q000235:genetics; D058112:Septins; D020825:T-Box Domain Proteins / Q000235:genetics; D019076:Transgenes / Q000235:genetics* / Q000502:physiology
chemical_list: D018797:Cell Cycle Proteins; C434113:GNB1L protein, human; D047908:Intracellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D019038:Platelet Glycoprotein GPIb-IX Complex; D011506:Proteins; D020825:T-Box Domain Proteins; C108625:TBX1 protein, human; C491573:Tbx1 protein, mouse; C109366:SEPTIN5 protein, human; C491612:Sept5 protein, mouse; D058112:Septins