Espin gene (ESPN) mutations associated with autosomal dominant hearing loss cause defects in microvillar elongation or organization

Francesca Donaudy ¹, Lili Zheng ², Romina Ficarella ¹, Ester Ballana ³, Massimo Carella ⁴, Salvatore Melchionda ⁴, Xavier Estivill ³, James Bartles ⁵ and Paolo Gasparini ^1*

¹ TIGEM-Telethon Institute of Genetics and Medicine, Naples, Italy
² Dept Cell and Mol Biol, Feinberg School of Med, Inst Neuroscience, Chicago, United States
³ Genes and Disease Program, Center for Genomic Regulation (CRG), Pompeu Fabra University, Barcelona, Spain
⁴ Servizio di Genetica Medica, IRCCS-Hospital, San Giovanni Rotondo, Italy
⁵ Dept Cell and Mol Biol, Feinberg School of Med, Inst for Neuroscience, Chicago, United States

^* To whom correspondence should be addressed. E-mail: gasparini{at}tigem.it.

Accepted 25 May 2005

Abstract

Introduction: Espins are actin-bundling proteins present in hair cell stereocilia. A recessive mutation in the espin gene (Espn) has been detected in the jerker mouse and causes deafness, vestibular dysfunction and hair cell degeneration. More recently mutations in the human espin gene (ESPN) have been described in two families affected by autosomal recessive hearing loss and vestibular areflexia.

Methods: An overall number of 450 hearing impaired subjects were analyzed for mutations in the espin gene by DHPLC on a WAVE Nucleic Acid Fragment Analysis System HSM (Transgenomic). To determine whether the mutated ESPN alleles affected the biological activity of the corresponding espin proteins in vivo, we investigated their ability to target and elongate the parallel actin bundles of brush border microvilli in transfected LLC-PK1-CL4 epithelial cells.

Results: Here, we report the identification of 4 additional ESPN mutations (S719R, D744N, R774Q, delK848) in patients affected by autosomal dominant hearing loss without vestibular involvement. For three mutated alleles clear abnormalities in microvillar length or distribution were obtained after investigating their ability to target and elongate the parallel actin bundles of brush border microvilli in transfected LLC-PK1-CL4 epithelial cells

Discussion: These results further strengthen the causative role of the espin gene in nonsyndromic hearing loss and add new insights into espin structure and function.

Keywords: ESPN, Espin, actin, autosomal dominant hearing loss, microvilli

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