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Human Molecular Genetics Advance Access originally published online on July 1, 2003
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Human Molecular Genetics, 2003, Vol. 12, No. 16 2041-2048
DOI: 10.1093/hmg/ddg216
© 2003 Oxford University Press

TBX1 is required for inner ear morphogenesis

Francesca Vitelli1, Antonella Viola1,3, Masae Morishima1, Tiziano Pramparo1, Antonio Baldini1,2 and Elizabeth Lindsay1,*

1Department of Pediatrics (Cardiology) and 2Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA and 3CEINGE Biotecnologie Avanzate, Via S. Pansini, 5, 80131, Naples, Italy

Received April 21, 2003; Revised June 13, 2003; Accepted June 23, 2003

TBX1 is thought to be a critical gene in the pathogenesis of del22q11/DiGeorge syndrome (DGS). Morphological abnormalities of the external ear and hearing impairment (conductive or sensorineural) affect the majority of patients. Here we show that homozygous mutation of the mouse homolog Tbx1 is associated with severe inner ear defects that prevent the formation of the cochlea and of the vestibulum. Consistent with phenotypic abnormalities, Tbx1 is expressed early in otocyst development in the otic epithelium and in the periotic mesenchyme. Tbx1 loss-of-function blocks inner ear development at early otocyst stage and after neurogenesis. Analysis of chimeras suggests that Tbx1 function is required in the otic epithelium cell autonomously, but abnormalities of the periotic mesenchyme indicate that the pathogenesis of the inner ear phenotype is complex. We propose a model where Tbx1 is required for expansion of a subpopulation of otic epithelial cells, which is required to form the vestibular and auditory organs. Our data suggest that Tbx1 deletion in del22q11 patients may cause not only external and middle ear defects but also sensorineural and vestibular phenotypes observed in these patients.

* To whom correspondence should be addressed at: Department of Pediatrics (Cardiology), Baylor College of Medicine-Feigin Center, 1102 Bates, Houston, TX, 77030, USA. Tel: +1 8328244162; Fax: +1 8328254153; Email: elindsay{at}bcm.tmc.edu


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