Diagnosis of the Genetic Causes of Deafness
Submitting Institution
University of SussexUnit of Assessment
Biological SciencesSummary Impact Type
TechnologicalResearch Subject Area(s)
Biological Sciences: Biochemistry and Cell Biology, Genetics
Medical and Health Sciences: Neurosciences
Summary of the impact
About one in 1,000 children are born deaf, and nearly half of all
children born deaf have a mutation in one of a number of different genes.
Work at Sussex in 1998 on the composition of the tectorial membrane, an
extracellular matrix of the inner ear, led to the identification of TECTA
as a deafness gene. Because of our research, mutations in TECTA are now
known to be a cause of autosomal dominant non-syndromic hearing loss, with
288 affected patients from 51 different families identified worldwide, to
date accounting for ~1-2 per cent of all autosomal dominant non-syndromic
hearing loss. Critically, TECTA is now one of 60 deafness genes included
in genetic tests for hereditary deafness.
Underpinning research
The cellular and molecular basis of hearing and deafness has been a focus
of research at Sussex for many years. The early work of Russell focused on
the electrophysiological properties of sensory hair cells in the cochlea,
and was later complemented by the work of Richardson — characterising the
key structures required for hearing at a molecular level — and that of
Kros, detailing the properties of the different ion channels present in
the sensory hair cells of the ear. This work has impacted upon an
understanding of how hearing happens, and has revealed the bases of some
of the many different forms of sensorineural hearing loss. Studies by
Richardson between 1987 and 1995 on the molecular composition of the
tectorial membrane, a specialised extracellular matrix that sits on top of
the sensory hair cells in the cochlea, revealed that it contains novel
matrix molecules that are unique to the inner ear. The subsequent
molecular cloning [see Section 3, R1] and mapping of a gene encoding one
of these matrix molecules at Sussex, and work performed together with a
group in Belgium, identified TECTA, a gene required for normal hearing, as
a deafness gene in 1998 [R2]. Mutations in TECTA cause both dominant and
recessive forms of deafness, and are now recognised as a cause of
autosomal dominant non-syndromic hearing loss [R3]. Mouse models for such
deafness-causing mutations made at Sussex have revealed the underlying
pathophysiology and isolated specific roles for this matrix in the hearing
process [R4]. A number of surface antigens that were first shown, at
Sussex, to be associated specifically with the mechano-sensory hair
bundles within the inner ear, were subsequently identified as the products
of additional deafness genes (PTPRQ, VLGR1 and PCDH15), and the properties
of many other hearing loss genes (e.g. MYO7A, STRC, OTOA, ACTG, CCDC50)
have been and continue to be characterised by the Sussex hearing team in
collaboration with other groups worldwide (R5). Additional studies at
Sussex have provided novel insights into the mechanisms of
antibiotic-induced otoxicity, revealing, unexpectedly, that the
aminoglycoside antibiotics, a commonly used class of medication,
selectively enter and accumulate in the sensory hair cells of the inner
ear via the transducer channels that are present in these cells [R6].
Key researchers and dates:
-
Guy Richardson FRS:
- 2009-present: University Professor, School of Life Sciences,
University of Sussex
- 2004-2009: Professorial Fellow, School of Life Sciences, University of
Sussex (Wellcome Trust University Award to G.P. Richardson)
- 1999-2004: Senior Research Fellow, School of Biological Sciences,
University of Sussex (PI with salary from Wellcome Trust programme grant
to G.P. Richardson)
- 1993-1999: Senior Research Fellow, School of Biological Sciences,
University of Sussex (PI with salary from MRC Programme grant to I.J.
Russell, G.P. Richardson and C.J. Kros)
-
Corne Kros:
- 2005-present: Professor of Neuroscience, School of Life Sciences,
University of Sussex
- 2000-2004: Reader in Neuroscience, School of Life Sciences, University
of Sussex
- 1997-2000: Lecturer then Reader (from 2000) in Physiology, Department
of Physiology, University of Bristol
- 1993-1996: Royal Society University Research Fellow, School of
Biological Sciences, University of Sussex
- 1989-1993: Research Fellow, School of Biological Sciences, University
of Sussex
-
Ian Russell:
- 1970-2010: Lecturer, Reader then Professor of Neuroscience, University
of Sussex
References to the research
R1 Legan, P.K., Rau, A., Keen, J.N. and Richardson, G.P. (1997)
`The mouse tectorins: modular matrix proteins of the inner ear homologous
to components of the sperm-egg adhesion system', Journal of Biological
Chemistry, 272(13): 8791-8801.
R2 Verhoeven, K., Van Laer, L., Kirschhofer, K., Legan, P.K.,
Hughes, D.C., Schatteman, I., Verstreken, M., Van Hauwe, P., Couke, P.,
Chen, A., Smith, R.J.H., Somers, .T, Offeciers, F.E., Van de Heymning, P.,
Richardson, G.P., Wachtler, F., Kimberling, W.J., Willems, P.J., Govaerts,
P.J. and Van Camp, G. (1998) `Mutations in human a-tectorin (TECTA) cause
autosomal dominant non-syndromic hearing impairment (DFNA8/DFNA12)', Nature
Genetics, 19(1): 60-62.
R3 Hildebrand, M.S., Morín, M., Meyer, N.C., Mayo, F.,
Modamio-Hoybjor, S., Mencía, A., Olavarrieta, L., Morales-Angulo, C.,
Nishimura, C.J., Workman, H., DeLuca, A.P., del Castillo, I., Taylor,
K.R., Tompkins, B., Goodman, C.W., Schrauwen, I., Wesemael, M.V., Lachlan,
K., Shearer, A.E., Braun, T.A., Huygen, P.L., Kremer, H., Van Camp, G.,
Moreno, F., Casavant, T.L., Smith, R.J. and Moreno-Pelayo, M.A. (2011)
`DFNA8/12 caused by TECTA mutations is the most identified subtype of
nonsyndromic autosomal dominant hearing loss', Human Mutation,
32(7): 825-834.
R4 Legan, P.K., Lukashkina, V.A., Goodyear, R.J., Lukashkin, A.N.,
Verhoeven, K., Van Camp, G., Russell, I.J. and Richardson, G.P. (2005) `A
deafness mutation isolates a second role for the tectorial membrane in
hearing', Nature Neuroscience, 8(8): 1035-1042.
R5 Lukashkin, A.N., Legan, P.K., Weddell, T.D.,
Lukashkina, V.A., Goodyear, R.J., Welstead, L., Petit, C.,
Russell, I.J. and Richardson, G.P. (2012) `A mouse model for human
deafness DFNB22 reveals that hearing impairment is due to a loss of inner
hair cell excitation', Proceedings of the National Academy of Sciences
of the Unites States of America, 109(47): 19351-19356.
R6 Marcotti, W., van Netten, S.M. and Kros, C.J. (2005) `The
aminoglycoside antibiotic dihydrostreptomycin rapidly enters mouse outer
hair cells through the mechano-electrical transducer channels', Journal
of Physiology, 567(2): 505-521.
Outputs can be supplied by the University on request.
Grants supporting, and obtained because of, the underpinning research:
• Russell, I.J., Richardson, G.P. and Kros, C.J. (1 October 1993-30
September 1998) MRC Programme Grant entitled `The molecular and cellular
basis of frequency selectivity and sensitivity in the cochlea' (Value
£1,494,217).
• Richardson, G.P. (6 June 1999-31 May 2004) Wellcome Trust Programme
Grant entitled 'Cell-surface and extracellular matrix molecules of the
inner ear: their roles in hearing, deafness, hair-cell regeneration and
deafness' (Value £895,712).
• Kros, C.J. (1 April 2003-31 March 2008) MRC Programme Grant entitled
`Functional significance and developmental acquisition of positional
gradients in normal and mutant mammalian hair cells' (Value £815,000).
• Richardson, G.P. (1 July 2004-31 January 2010) Wellcome Trust
University Award entitled `Extracellular-matrix and cell-surface molecules
of the inner ear: roles in hearing and hair-bundle development' (Value
£1,181,844).
• Petit, C. et al. (1 December 2004-31 November 2009) European
Union Consortium Grant entitled `EuroHear' (Value for Sussex [PIs Kros and
Richardson] £670,363).
• Richardson, G.P. (1 February 2010-31 January 2015) Wellcome Trust
Programme Grant entitled `The tectorial membrane and the sensory hair
bundles of the inner ear: mechanisms of development and effects of
deafness-related mutations' (Value £1,268,129).
• Kros, C.J. (PI) with Moore, A.L., Richardson, G.P. and Ward, S. (1
April 2013-31 March 2018) MRC Research Grant entitled `Mechanisms of
aminoglycoside ototoxicity and drug-damage repair in sensory hair cells:
towards the design of otoprotective strategies' (Value £2,337,458).
Details of the impact
The underpinning research increased our understanding of cochlear
function and dysfunction, led to the identification of TECTA as a deafness
gene, and revealed roles for many others (e.g. MYO7A, PCDH15, PTPRQ, OTOA
& VLGR1). TECTA and the additional genes now comprise a subset of the
60 deafness genes included on OtoSCOPE, a comprehensive genetic test
implemented in 2010 and now used for the diagnosis of hereditary deafness
by the clinical community [see Section 5, C1, C2 and C3]. Dr Guy van Camp
writes: `The identification of deafness genes has led to improved DNA
diagnostics. DNA diagnostics for deafness in children is very important,
as it has the potential of providing valuable information on therapeutic
options, the future evolution of the hearing loss, the development of
additional symptoms (such as blindness in Usher syndrome) later in life,
the recurrence risk and guilt relief for parents'.
Between 2008 and 2012, mutations in TECTA have been identified as the
cause of hereditary hearing loss in 288 patients from 51 different
families worldwide thus far, and the OtoScope screening platform, in the
first 100 people tested during this period, has identified two novel
missense mutations in TECTA that cause recessive deafness. An
understanding of the cause of deafness in these families enables genetic
counselling and provides information regarding the suitability of
different corrective measures, with hearing aids or cochlear implants
being likely therapies. The work has also changed our understanding of how
aminoglycoside antibiotics selectively accumulate in and cause damage to
sensory hair cells. It thus informs on potential measures to prevent the
ototoxic side effects of an otherwise clinically useful class of drug,
such as reinforcing the case for a once-daily dosing regime and trying to
design novel drugs that could be co-administered with the aminoglycosides
and that compete with the antibiotics for the entry mechanism into the
sensory hair cells (MRC Research Grant by Kros et al.). As a
result, we have advised clinicians, during the REF period, about the
clinical implications for patients treated with these antibiotics (see
Section 5, C4).
Sources to corroborate the impact
C1 Letter from Dr Guy van Camp, Department of Medical Genetics,
University of Antwerp.
C2 Dr Miguel Angel Moreno Pelayo, Unidad Genética Molecular,
Hospital Ramón y Cajal. This source can corroborate that mutations in
TECTA are a common cause of autosomal dominant non-syndromic hearing loss.
C3 OtoScope web-site;
http://www.healthcare.uiowa.edu/labs/morl/otoscope/home.html
C4 Email from Head of BSUH Audiological Services, to C.J. Kros
(dated 19 August 2010).