Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Orphanet Journal of Rare Diseases
Published in: Orphanet Journal of Rare Diseases 1/2015

Open Access 01-12-2015 | Research

EPS8L2 is a new causal gene for childhood onset autosomal recessive progressive hearing loss

Authors: Malika Dahmani, Fatima Ammar-Khodja, Crystel Bonnet, Gaelle M. Lefèvre, Jean-Pierre Hardelin, Hassina Ibrahim, Zahia Mallek, Christine Petit

Published in: Orphanet Journal of Rare Diseases | Issue 1/2015

Login to get access

Abstract

Background

More than 70 % of the cases of congenital deafness are of genetic origin, of which approximately 80 % are non-syndromic and show autosomal recessive transmission (DFNB forms). To date, 60 DFNB genes have been identified, most of which cause congenital, severe to profound deafness, whereas a few cause delayed progressive deafness in childhood. We report the study of two Algerian siblings born to consanguineous parents, and affected by progressive hearing loss.

Method

After exclusion of GJB2 (the gene most frequently involved in non-syndromic deafness in Mediterranean countries), we performed whole-exome sequencing in one sibling.

Results

A frame-shift variant (c.1014delC; p.Ser339Alafs*15) was identified in EPS8L2, encoding Epidermal growth factor receptor Pathway Substrate 8 L2, a protein of hair cells’ stereocilia previously implicated in progressive deafness in the mouse. This variant predicts a truncated, inactive protein, or no protein at all owing to nonsense-mediated mRNA decay. It was detected at the homozygous state in the two clinically affected siblings, and at the heterozygous state in the unaffected parents and one unaffected sibling, whereas it was never found in a control population of 150 Algerians with normal hearing or in the Exome Variant Server database.

Conclusion

Whole-exome sequencing allowed us to identify a new gene responsible for childhood progressive hearing loss transmitted on the autosomal recessive mode.
Literature
1.
Petit C, Levilliers J, Hardelin J-P. Molecular genetics of hearing loss. Annu Rev Genet. 2001;35:589–646.CrossRefPubMed
2.
Morton NE. Genetic epidemiology of hearing impairment. Annu NY Acad Sci. 1991;630:16–31.CrossRef
3.
4.
Piatto VB, Secches LV, Arroyo MAS, Lopes ACP, Maniglia JV. Nonsyndromic deafness - Molecular update. Open Biol J. 2009;2:80–90.CrossRef
5.
Denoyelle F, Marlin S, Weil D, Moatti L, Chauvin F, Garabedian EN, et al. Clinical features of the prevalent form of childhood deafness, DFNB1, due to a connexin-26 gene defect: implications for genetic counselling. Lancet. 1999;353:1298–303.CrossRefPubMed
6.
Frei K, Ramsebner R, Lucas T, Hamader G, Szuhai K, Weipoltshammer K, et al. GJB2 mutations in hearing impairment: identification of a broad clinical spectrum for improved genetic counseling. Laryngoscope. 2005;115:461–5.CrossRefPubMed
7.
Ammar-Khodja F, Makrelouf M, Malek R, Ibrahim H, Zenati A. Frequency of the 35 delG allele causing non-syndromic recessive deafness in the Algerian patients. Genet Couns. 2007;18:383–91.PubMed
8.
Ammar-Khodja F, Bonnet C, Dahmani M, Ouhab S, Lefèvre GM, Ibrahim H, et al. Diversity of the causal genes in hearing impaired Algerian individuals identified by whole exome sequencing. Mol Genet Genom Med 2015;3:189-96.
9.
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;21:3835–44.CrossRefPubMed
10.
del Castillo FJ, Rodriguez‐Ballesteros M, Alvarez A, Hutchin T, Leonardi E, de Oliveira CA, et al. A novel deletion involving the connexin‐30 gene, del(GJB6‐d13s1854), found in trans with mutations in the GJB2 gene (connexin‐26) in subjects with DFNB1 non‐syndromic hearing impairment. J Med Genet. 2005;42:588–94.PubMedCentralCrossRefPubMed
11.
Furness DN, Johnson SL, Manor U, Ruttiger L, Tocchetti A, Offenhauser N, et al. 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;110:13898–903.PubMedCentralCrossRefPubMed
12.
Abe S, Usami S, Hoover DM, Cohn E, Shinkawa H, Kimberling WJ. Fluctuating sensorineural hearing loss associated with enlarged vestibular aqueduct maps to 7q31, the region containing the Pendred syndrome gene. Am J Med Genet. 1999;82:322–8.CrossRefPubMed
13.
Bladwin CT, Weiss S, Farrer LA, De Stefano AL, Adair R, Franklyn B, et al. Linkage of congenital, recessive deafness (DFNB4) to chromosome 7q31 and evidence for genetic heterogeneity in the Middle Eastern Druze population. Hum Mol Genet. 1995;4:1637–42.CrossRef
14.
Walsh T, Walsh V, Vreugde S, Hertzano R, Shahin H, Haika S, et al. From flies' eyes to our ears: mutations in a human class III myosin cause progressive nonsyndromic hearing loss DFNB30. Proc Natl Acad Sci U S A. 2002;99:7518–23.PubMedCentralCrossRefPubMed
15.
Grillet N, Schwander M, Hildebrand MS, Sczaniecka A, Kolatkar A, Velasco J, et al. Mutations in LOXHD1, an evolutionarily conserved stereociliary protein, disrupt hair cell function in mice and cause progressive hearing loss in humans. Am J Hum Genet. 2009;85:328–37.PubMedCentralCrossRefPubMed
16.
Delmaghani S, del Castillo FG, Michel V, Leibovici M, Aghaie A, Ron U, et al. Mutations in the gene encoding pejvakin, a newly identified protein of the afferent auditory pathway, cause DFNB59 auditory neuropathy. Nat Genet. 2006;38:770–8.CrossRefPubMed
17.
Schwander M, Sczaniecka A, Grillet N, Bailey JS, Avenarius M, Najmabadi H, et al. A forward genetics screen in mice identifies recessive deafness traits and reveals that pejvakin is essential for outer hair cell function. J Neurosci. 2007;27:2163–75.CrossRefPubMed
18.
Ebermann I, Walger M, Scholl HPN, Issa PC, Luke C, Nurnberg G, et al. Truncating mutation of the DFNB59 gene causes cochlear hearing impairment and central vestibular dysfunction. Hum Mutat. 2007;28:571–7.CrossRefPubMed
19.
Chaleshtori MH, Simpson MA, Farrokhi E, Dolati M, Rad LH, Geshnigani SA, et al. Novel mutations in the pejvakin gene are associated with autosomal recessive non-syndromic hearing loss in Iranian families. Clin Genet. 2007;72:261–3.CrossRef
20.
Collin RWJ, Kalay E, Oostrik J, Caylan R, Wollnik B, Arslan S, et al. Involvement of DFNB59 mutations in autosomal recessive nonsyndromic hearing impairment. Hum Mutat. 2007;28:718–23.CrossRefPubMed
21.
Huang M, Duman D, Cengiz FB, Bademci G, Tokgöz-Yilmaz S, Hişmi B, et al. A truncating mutation in SERPINB6 is associated with autosomal recessive nonsyndromic sensorineural hearing loss. Am J Hum Genet. 2010;86:797–804.PubMedCentralCrossRefPubMed
22.
Rehman AU, Morell RJ, Belyantseva IA, Khan SY, Boger ET, Shahzad M, et al. Targeted capture and next-generation sequencing identifies C9orf75, encoding taperin, as the mutated gene in nonsyndromic deafness DFNB79. Am J Hum Genet. 2010;86:378–88.PubMedCentralCrossRefPubMed
23.
Li Y, Pohl E, Boulouiz R, Schraders M, Nurnberg G, Charif M, et al. Mutations in TPRN cause a progressive form of autosomal-recessive nonsyndromic hearing loss. Am J Hum Genet. 2010;86:479–84.PubMedCentralCrossRefPubMed
24.
Veske A, Oehlmann R, Younus F, Mohyuddin A, Müller-Myhsok B, Qasim Mehdi S, et al. Autosomal recessive non-syndromic deafness locus (DFNB8) maps on chromosome 21q22 in a large consanguineous kindred from Pakistan. Hum Mol Genet. 1996;5:165–8.CrossRefPubMed
25.
Scott HS, Kudoh J, Wattenhofer M, Shibuya K, Berry A, Chrast R, et al. Insertion of beta-satellite repeats identifies a transmembrane protease causing both congenital and childhood onset autosomal recessive deafness. Nat Genet. 2001;27:59–63.PubMed
26.
Charizopoulou N, Lelli A, Schraders M, Ray K, Hildebrand MS, Ramesh A, et al. Gipc3 mutations associated with audiogenic seizures and sensorineural hearing loss in mouse and human. Nat Commun. 2011;2:201–12.PubMedCentralCrossRefPubMed
27.
Horn HF, Brownstein Z, Lenz DR, Shivatzki S, Dror AA, Dagan-Rosenfeld O, et al. The LINC complex is essential for hearing. J Clin Invest. 2013;123:740–50.PubMedCentralPubMed
28.
29.
Seco CZ, Oonk AM, Domınguez-Ruiz M, Draaisma JMT, Gandi M, Oostrik J, et al. Progressive hearing loss and vestibular dysfunction caused by a homozygous nonsense mutation in CLIC5. Eur J Hum Genet. 2014;23:189–94.CrossRefPubMed
30.
de Heer AM, Collin RW, Huygen PL, Schraders M, Oostrik J, Rouwette M, et al. Progressive sensorineural hearing loss and normal vestibular function in a Dutch DFNB7/11 family with a novel mutation in TMC1. Audiol Neurootol. 2011;16:93–105.CrossRefPubMed
31.
Mori K, Miyanohara I, Moteki H, Nishio SY, Kurono Y, Usami SI. Novel Mutations in GRXCR1 at DFNB25 lead to progressive hearing loss and dizziness. Ann Otol Rhinol Laryngol. 2015;0003489415575061.
32.
Ichinose A, Moteki H, Hattori M, Nishio SY, Usami SI. Novel mutations in LRTOMT associated with moderate progressive hearing loss in autosomal recessive inheritance. Ann Otol Rhinol Laryngol. 2015;0003489415575043.
33.
Offenhäuser N, Borgonovo A, Disanza A, Romano P, Ponzanelli I, Iannolo G, et al. The eps8 family of proteins links growth factor stimulation to actin reorganization generating functional redundancy in the Ras/Rac pathway. Mol Biol Cell. 2004;15:91–8.PubMedCentralCrossRefPubMed
34.
Zampini V, Ruttiger L, Johnson SL, Franz C, Furness DN, Waldhaus J, et al. Eps8 regulates hair bundle length and functional maturation of mammalian auditory hair cells. PLoS Biol. 2011;9, e1001048.PubMedCentralCrossRefPubMed
35.
Behlouli A, Bonnet C, Abdi S, Bouaita A, Lelli A, Hardelin J-P, et al. EPS8, encoding an actin-binding protein of cochlear hair cell stereocilia, is a new causal gene for autosomal recessive profound deafness. Orph J Rar Dis. 2014;9:55.CrossRef
36.
Manor U, Disanza A, Grati MH, Andrade L, Lin H, Di Fiore PP, et al. Regulation of stereocilia length by myosin XVa and whirlin depends on the actin-regulatory protein Eps8. Curr Biol. 2011;21:167–72.PubMedCentralCrossRefPubMed
Metadata
Title
EPS8L2 is a new causal gene for childhood onset autosomal recessive progressive hearing loss
Authors
Malika Dahmani
Fatima Ammar-Khodja
Crystel Bonnet
Gaelle M. Lefèvre
Jean-Pierre Hardelin
Hassina Ibrahim
Zahia Mallek
Christine Petit
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Orphanet Journal of Rare Diseases / Issue 1/2015
Electronic ISSN: 1750-1172
DOI
https://doi.org/10.1186/s13023-015-0316-8

Other articles of this Issue 1/2015

Orphanet Journal of Rare Diseases 1/2015 Go to the issue

Review

Recommendations for the development of rare disease drugs using the accelerated approval pathway and for qualifying biomarkers as primary endpoints

Position statement

A proposed definition of rare diseases for China: from the perspective of return on investment in new orphan drugs

Research

Next generation sequencing in a large cohort of patients presenting with neuromuscular disease before or at birth

Research

Prevalence of pemphigus and pemphigoid autoantibodies in the general population

Research

Comprehensive molecular diagnosis of 67 Chinese Usher syndrome probands: high rate of ethnicity specific mutations in Chinese USH patients

Research

Effectiveness of agalsidase alfa enzyme replacement in Fabry disease: cardiac outcomes after 10 years’ treatment