EPS8, encoding an actin-binding protein of cochlear hair cell stereocilia, is a new causal gene for autosomal recessive profound deafness

Orphanet Journal of Rare Diseases

Christine Petit⁵  Akila Zenati⁶  Mohamed Makrelouf⁶  Kamel Boudjelida⁸  Hayet Lebdi¹  Ahmed Cheknane¹  Malek Louha⁴  Yahia Rous⁴  Cataldo Schietroma²  Jean-Pierre Hardelin³  Andrea Lelli³  Aïcha Bouaita²  Samia Abdi⁷  Crystel Bonnet²  Asma Behlouli⁶ 

[1] Service ORL, Centre Hospitalier universitaire de Blida, Blida, Algérie;INSERM UMRS1120, UPMC, Institut de la Vision, Paris, France;Unité de Génétique et Physiologie de l’Audition, INSERM UMRS1120, Institut Pasteur, Paris, France;Service de Biochime et de Biologie Moléculaire, Hôpital Armand Trousseau, APHP, Paris, France;Collège de France, Paris, France;Laboratoire de Biochimie Génétique, Service de Biologie - CHU de Bab El Oued, Université d’Alger 1, Alger, Algérie;Génétique et Biologie, Centre Hospitalier universitaire de Blida, Université Saad Dahleb, Blida, Algérie;Service Ophtalmologie, Centre Hospitalier universitaire de Blida, Blida, Algérie

关键词: Actin dynamics;    Stereocilia bundle;    Whole-exome sequencing;    Congenital deafness;    Epidermal growth factor receptor pathway substrate 8;   

Others  :  863196
DOI  :  10.1186/1750-1172-9-55

 received in 2014-01-14, accepted in 2014-04-08,  发布年份 2014

【 摘 要 】

Background

Almost 90% of all cases of congenital, non-syndromic, severe to profound inherited deafness display an autosomal recessive mode of transmission (DFNB forms). To date, 47 causal DFNB genes have been identified, but many others remain to be discovered. We report the study of two siblings born to consanguineous Algerian parents and affected by isolated, profound congenital deafness.

Method

Whole-exome sequencing was carried out on these patients after a failure to identify mutations in the DFNB genes frequently involved.

Results

A biallelic nonsense mutation, c.88C > T (p.Gln30*), was identified in EPS8 that encodes epidermal growth factor receptor pathway substrate 8, a 822 amino-acid protein involved in actin dynamics. This mutation predicts a truncated inactive protein or no protein at all. The mutation was also present, in the heterozygous state, in one clinically unaffected sibling and in both unaffected parents, and was absent from the other two unaffected siblings. It was not found in 120 Algerian normal hearing control individuals or in the Exome Variant Server database. EPS8 is an F-actin capping and bundling protein. Mutant mice lacking EPS8 (Eps8^−/− mice), which is present in the hair bundle, the sensory antenna of the auditory sensory cells that operate the mechano-electrical transduction, are also profoundly deaf and have abnormally short hair bundle stereocilia.

Conclusion

This new DFNB form is likely to arise from abnormal hair bundles resulting in compromised detection of physiological sound pressures.

【 授权许可】

   
2014 Behlouli et al.; licensee BioMed Central Ltd.

【 图 表 】

【 参考文献 】

• [1]van Camp G, Willems PJ, Smith RJ: Nonsyndromic hearing impairment: unparalleled heterogeneity. Am J Hum Genet 1997, 60:758-764.
• [2]Brownstein Z, Bhonker Y, Avraham KB: High-throughput sequencing to decipher the genetic heterogeneity of deafness. Genome Biol 2012, 13:245. BioMed Central Full Text
• [3]Guilford P, Ayadi H, Blanchard S, Chaib H, le Paslier D, Weissenbach J, Drira M, Petit C: A human gene responsible for neurosensory, non-syndromic recessive deafness is a candidate homologue of the mouse sh-1 gene. Hum Mol Genet 1994, 3:989-993.
• [4]Ben Arab S, Hmani M, Denoyelle F, Boulila-Elgaied A, Chardenoux S, Hachicha S, Petit C, Ayadi H: Mutations of GJB2 in three geographic isolates from northern Tunisia: evidence for genetic heterogeneity within isolates. Clin Genet 2000, 57:439-443.
• [5]Zwaenepoel I, Mustapha M, Leibovici M, Verpy E, Goodyear R, Liu XZ, Nouaille S, Nance WE, Kanaan M, Avraham KB, Tekaia F, Loiselet J, Lathrop M, Richardson G, Petit C: Otoancorin, an inner ear protein restricted to the interface between the apical surface of sensory epithelia and their overlying acellular gels, is defective in autosomal recessive deafness DFNB22. Proc Natl Acad Sci U S A 2002, 99:6240-6245.
• [6]Abidi O, Boulouiz R, Nahili H, Ridal M, Alami MN, Tlili A, Rouba H, Masmoudi S, Chafik A, Hassar M, Barakat A: GJB2 (connexin 26) gene mutations in Moroccan patients with autosomal recessive non-syndromic hearing loss and carrier frequency of the common GJB2-35delG mutation. Int J Pediatr Otorhinolaryngol 2007, 71:1239-1245.
• [7]Delmaghani S, Aghaie A, Michalski N, Bonnet C, Weil D, Petit C: Defect in the gene encoding the EAR/EPTP domain-containing protein TSPEAR causes DFNB98 profound deafness. Hum Mol Genet 2012, 21:3835-3844.
• [8]Sahly I, Dufour E, Schietroma C, Michel V, Bahloul A, Perfettini I, Pepermans E, Estivalet A, Carette D, Aghaie A, Ebermann I, Lelli A, Iribarne M, Hardelin JP, Weil D, Sahel JA, El-Amraoui A, Petit C: Localization of Usher 1 proteins to the photoreceptor calyceal processes, which are absent from mice. J Cell Biol 2012, 199:381-399.
• [9]Baker KE, Parker R: Nonsense-mediated mRNA decay: terminating erroneous gene expression. Curr Opin Cell Biol 2004, 16:293-299.
• [10]Manor U, Disanza A, Grati M, Andrade L, Lin H, di Fiore PP, Scita G, Kachar B: Regulation of stereocilia length by myosin XVa and whirlin depends on the actin-regulatory protein Eps8. Curr Biol 2011, 21:167-172.
• [11]Zampini V, Ruttiger L, Johnson SL, Franz C, Furness DN, Waldhaus J, Xiong H, Hackney CM, Holley MC, Offenhauser N, Di Fiore PP, Knipper M, Masetto S, Marcotti W: Eps8 regulates hair bundle length and functional maturation of mammalian auditory hair cells. PLoS Biol 2011, 9:e1001048.
• [12]Disanza A, Carlier MF, Stradal TE, Didry D, Frittoli E, Confalonieri S, Croce A, Wehland J, di Fiore PP, Scita G: Eps8 controls actin-based motility by capping the barbed ends of actin filaments. Nat Cell Biol 2004, 6:1180-1188.
• [13]Maa M-C, Leu T-H: EPS8, an adaptor protein acts as an oncoprotein in human cancer. Carcinogenesis, Dr Kathryn Tonissen (Ed) 2013. ISBN: 978-953-51-0945-7, InTech, DOI: 10.5772/54906. Available from: http://www.intechopen.com/books/carcinogenesis/eps8-an-adaptor-protein-acts-as-an-oncoprotein-in-human-cancer webcite
• [14]Furness DN, Johnson SL, Manor U, Ruttiger L, Tocchetti A, Offenhauser N, Olt J, Goodyear RJ, Vijayakumar S, Dai Y, Hackney CM, Franz C, Di Fiore PP, Masetto S, Jones SM, Knipper M, Holley MC, Richardson GP, Kachar B, Marcotti W: Progressive hearing loss and gradual deterioration of sensory hair bundles in the ears of mice lacking the actin-binding protein Eps8L2. Proc Natl Acad Sci U S A 2013, 110:13898-13903.
• [15]Fettiplace R, Hackney CM: The sensory and motor roles of auditory hair cells. Nat Rev Neurosci 2006, 7:19-29.
• [16]Hudspeth AJ: How the ear’s works work: mechanoelectrical transduction and amplification by hair cells. C R Biol 2005, 328:155-162.
• [17]Petit C, Richardson GP: Linking genes underlying deafness to hair-bundle development and function. Nat Neurosci 2009, 12:703-710.
• [18]Welsch T, Endlich K, Giese T, Buchler MW, Schmidt J: Eps8 is increased in pancreatic cancer and required for dynamic actin-based cell protrusions and intercellular cytoskeletal organization. Cancer Lett 2007, 255:205-218.
• [19]Probst FJ, Fridell RA, Raphael Y, Saunders TL, Wang A, Liang Y, Morell RJ, Touchman JW, Lyons RH, Noben-Trauth K, Friedman TB, Camper SA: Correction of deafness in shaker-2 mice by an unconventional myosin in a BAC transgene. Science 1998, 280:1444-1447.
• [20]Mburu P, Mustapha M, Varela A, Weil D, El-Amraoui A, Holme RH, Rump A, Hardisty RE, Blanchard S, Coimbra RS, Perfettini I, Parkinson N, Mallon AM, Glenister P, Rogers MJ, Paige AJ, Moir L, Clay J, Rosenthal A, Liu XZ, Blanco G, Steel KP, Petit C, Brown SD: Defects in whirlin, a PDZ domain molecule involved in stereocilia elongation, cause deafness in the whirler mouse and families with DFNB31. Nat Genet 2003, 34:421-428.
• [21]Audo I, Bujakowska K, Mohand-Said S, Tronche S, Lancelot ME, Antonio A, Germain A, Lonjou C, Carpentier W, Sahel JA, Bhattacharya S, Zeitz C: A novel DFNB31 mutation associated with Usher type 2 syndrome showing variable degrees of auditory loss in a consanguineous Portuguese family. Mol Vis 2011, 17:1598-1606.
• [22]van Wijk E, van der Zwaag B, Peters T, Zimmermann U, te Brinke H, Kersten FF, Marker T, Aller E, Hoefsloot LH, Cremers CW, Cremers FP, Wolfrum U, Knipper M, Roepman R, Kremer H: The DFNB31 gene product whirlin connects to the Usher protein network in the cochlea and retina by direct association with USH2A and VLGR1. Hum Mol Genet 2006, 15:751-765.