Nature Genetics
34, 421 - 428 (2003)
Published online: 29 June 2003; | doi:10.1038/ng1208
Defects in whirlin, a PDZ domain molecule involved in stereocilia elongation, cause deafness in the whirler mouse and families with DFNB31Philomena Mburu1, 8, Mirna Mustapha2, 8, Anabel Varela1, 7, 8, Dominique Weil2, 8, Aziz El-Amraoui2, 8, Ralph H Holme3, Andreas Rump4, 5, Rachel E Hardisty1, Stéphane Blanchard2, Roney S Coimbra2, Isabelle Perfettini2, Nick Parkinson1, Ann-Marie Mallon1, Pete Glenister1, Mike J Rogers3, Adam J Paige1, Lee Moir1, Jo Clay1, Andre Rosenthal4, 5, Xue Zhong Liu6, Gonzalo Blanco1, Karen P Steel3, Christine Petit2
& Steve D M Brown11
MRC Mammalian Genetics Unit and UK Mouse Genome Centre, Harwell, Oxon OX11 ORD, UK. 2
Unité de Génétique des Déficits Sensoriels, INSERM U587, Institut Pasteur, 25 rue du Dr. Roux, 75724 Paris cedex 15, France. 3
MRC Institute of Hearing Research, University of Nottingham, Nottingham, NG7 2RD, UK. 4
MetaGen Pharmaceuticals Gmbh, Oudenarder Str 16, Aufgang 9, 13347 Berlin, Germany. 5
Institute of Molecular Biotechnology, Department of Genome Analysis, 07445 Jena, Germany. 6
Department of Otolaryngology, University of Miami, Florida 33101, USA. 7
Present address: Cancer Cell Biology, Imperial School Of Science, Technology and Medicine, Hammmersmith Campus, Du Cane Road, W12 0NN, UK. 8
These authors contributed equally to this work.
Correspondence should be addressed to Christine Petit cpetit@pasteur.frThe whirler mouse mutant (wi) does not respond to sound stimuli, and detailed ultrastructural analysis of sensory hair cells in the organ of Corti of the inner ear indicates that the whirler gene encodes a protein involved in the elongation and maintenance of stereocilia in both inner hair cells (IHCs) and outer hair cells (OHCs). BAC-mediated transgene correction of the mouse phenotype and mutation analysis identified the causative gene as encoding a novel PDZ protein called whirlin. The gene encoding whirlin also underlies the human autosomal recessive deafness locus DFNB31. In the mouse cochlea, whirlin is expressed in the sensory IHC and OHC stereocilia. Our findings suggest that this novel PDZ domain−containing molecule acts as an organizer of submembranous molecular complexes that control the coordinated actin polymerization and membrane growth of stereocilia.
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