title: EPS8, encoding an actin-binding protein of cochlear hair cell stereocilia, is a new causal gene for autosomal recessive profound deafness.
abstract: 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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  This new DFNB form is likely to arise from abnormal hair bundles resulting in compromised detection of physiological sound pressures.
authors.forename: Asma
authors.initials: A
authors.lastname: Behlouli
authors.forename: Crystel
authors.initials: C
authors.lastname: Bonnet
authors.forename: Samia
authors.initials: S
authors.lastname: Abdi
authors.forename: Aïcha
authors.initials: A
authors.lastname: Bouaita
authors.forename: Andrea
authors.initials: A
authors.lastname: Lelli
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Hardelin
authors.forename: Cataldo
authors.initials: C
authors.lastname: Schietroma
authors.forename: Yahia
authors.initials: Y
authors.lastname: Rous
authors.forename: Malek
authors.initials: M
authors.lastname: Louha
authors.forename: Ahmed
authors.initials: A
authors.lastname: Cheknane
authors.forename: Hayet
authors.initials: H
authors.lastname: Lebdi
authors.forename: Kamel
authors.initials: K
authors.lastname: Boudjelida
authors.forename: Mohamed
authors.initials: M
authors.lastname: Makrelouf
authors.forename: Akila
authors.initials: A
authors.lastname: Zenati
authors.affiliation: INSERM UMRS1120, UPMC, Institut de la Vision, Paris, France. christine.petit@pasteur.fr.
authors.forename: Christine
authors.initials: C
authors.lastname: Petit
mesh_terms: D000199:Actins / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D059472:Exome; D005260:Female; D006198:Hair Cells, Auditory / Q000378:metabolism*; D006319:Hearing Loss, Sensorineural / Q000235:genetics*; D006801:Humans; D008297:Male; D051379:Mice; D010375:Pedigree; D059547:Stereocilia / Q000378:metabolism*
chemical_list: D000199:Actins; D048868:Adaptor Proteins, Signal Transducing; D017931:DNA Primers; C489989:EPS8 protein, human
references.citation: Nat Rev Neurosci. 2006 Jan;7(1):19-29
references.pmid: 16371947
references.citation: PLoS Biol. 2011 Apr;9(4):e1001048
references.pmid: 21526224
references.citation: Proc Natl Acad Sci U S A. 2002 Apr 30;99(9):6240-5
references.pmid: 11972037
references.citation: Int J Pediatr Otorhinolaryngol. 2007 Aug;71(8):1239-45
references.pmid: 17553572
references.citation: Science. 1998 May 29;280(5368):1444-7
references.pmid: 9603735
references.citation: Curr Opin Cell Biol. 2004 Jun;16(3):293-9
references.pmid: 15145354
references.citation: Nat Cell Biol. 2004 Dec;6(12):1180-8
references.pmid: 15558031
references.citation: Hum Mol Genet. 2012 Sep 1;21(17):3835-44
references.pmid: 22678063
references.citation: J Cell Biol. 2012 Oct 15;199(2):381-99
references.pmid: 23045546
references.citation: Proc Natl Acad Sci U S A. 2013 Aug 20;110(34):13898-903
references.pmid: 23918390
references.citation: C R Biol. 2005 Feb;328(2):155-62
references.pmid: 15771001
references.citation: Nat Neurosci. 2009 Jun;12(6):703-10
references.pmid: 19471269
references.citation: Am J Hum Genet. 1997 Apr;60(4):758-64
references.pmid: 9106521
references.citation: Clin Genet. 2000 Jun;57(6):439-43
references.pmid: 10905664
references.citation: Curr Biol. 2011 Jan 25;21(2):167-72
references.pmid: 21236676
references.citation: Nat Genet. 2003 Aug;34(4):421-8
references.pmid: 12833159
references.citation: Hum Mol Genet. 2006 Mar 1;15(5):751-65
references.pmid: 16434480
references.citation: Cancer Lett. 2007 Oct 8;255(2):205-18
references.pmid: 17537571
references.citation: Mol Vis. 2011;17:1598-606
references.pmid: 21738389
references.citation: Hum Mol Genet. 1994 Jun;3(6):989-93
references.pmid: 7951250
references.citation: Genome Biol. 2012 May 29;13(5):245
references.pmid: 22647651