Hearing

The IMPC is hunting unknown genes responsible for hearing loss by screening knockout mice

  • 360 million people worldwide live with mild to profound hearing loss
  • 70% hearing loss occurs as an isolated condition (non-syndromic) and 30% with additional phenotypes (syndromic)
  • The vast majority of genes responsible for hearing loss are unknown

Approach

In order to identify the function of genes, the consortium uses a series of standardised protocols as described in IMPReSS (International Mouse Phenotyping Resource of Standardised Screens).

Hearing capacity is assessed using an Auditory Brain Stem response (ABR) test conducted at 14 weeks of age. Hearing is assessed at five frequencies – 6kHz, 12kHz, 18kHz, 24kHz and 30kHz – as well as a broadband click stimulus. Increased thresholds are indicative of abnormal hearing. Abnormalities in adult ear morphology are recorded as part of the Combined SHIRPA and Dysmorphology (CSD) protocol, which includes a response to a click box test (absence is indicative of a strong hearing deficit) and visual inspection for behavioural signs that may indicate vestibular dysfunction e.g. head bobbing or circling.

Procedures that can lead to relevant phenotype associations

Young Adult:

IMPC Deafness Publication

Hearing loss investigated in 3,006 knockout mouse lines

A large scale hearing loss screen reveals an extensive unexplored genetic landscape for auditory dysfunction
Nature Communications (released 12/10/2017)

  • 67 genes identified as candidate hearing loss genes
  • 52 genes are not previously associated with hearing loss and encompass a wide range of functions from structural proteins to transcription factors
  • Among the novel candidate genes, Atp2b1 is expressed in the inner ear and Sema3f plays a role in sensory hair cell innervation in the cochlea
  • The IMPC will continue screening for hearing loss mutants in its second 5 year phase

Press releases: EMBL-EBI | MRC | IMPC

Methods

Response data from the Auditory Brain Stem response (ABR) test was used – hearing at five frequencies, 6kHz, 12kHz, 18kHz, 24kHz and 30kHz was measured.

  • Control wildtype mice from each phenotypic centre included, matched for gender, age, phenotypic pipeline and metadata (e.g. instrument)
  • Our production statistical approach that automatically detects mutants with abnormal hearing was manually curated to yield 67 genes with profound hearing loss

Gene table

Supplementary Material

Sixty-seven deafness genes were identified:

Gene symbol Zygosity Status Hearing loss
A730017C20Rik Hom Novel Severe
Aak1 Hom Novel High
Acsl4 Hom Novel High
Acvr2a Hom Novel Mild
Adgrb1 Hom Novel Mild
Adgrv1 Hom Known Severe
Ahsg Hom Novel High
Ankrd11 Het Novel Mild
Ap3m2 Hom Novel Mild
Ap3s1 Hom Novel Mild
Atp2b1 Het Novel Low
B020004J07Rik Hom Novel Low
Baiap2l2 Hom Novel Mild
Ccdc88c Hom Novel High
Ccdc92 Hom Novel Mild
Cib2 Hom Known Severe
Clrn1 Hom Known Severe
Col9a2 Hom Known Severe
Cyb5r2 Hom Novel Mild
Dnase1 Hom Novel High
Duoxa2 Hom Novel Severe
Elmod1 Hom Known Severe
Emb Hom Novel High
Eps8l1 Hom Novel Severe
Ewsr1 Het Novel High
Gata2 Het Known Low
Gga1 Hom Novel Mild
Gipc3 Hom Known Severe
Gpr152 Hom Novel High
Gpr50 Hom Novel Low
Ikzf5 Hom Novel High
Il1r2 Hom Novel Low
Ildr1 Hom Known Severe
Klc2 Hom Novel Severe
Klhl18 Hom Novel Low
Marveld2 Hom Known Severe
Med28 Het Novel Low
Mpdz Hom Novel Mild
Myh1 Hom Novel Mild
Myo7a Hom Known Severe
Nedd4l Hom Novel Severe
Nfatc3 Het Novel Low
Nin Hom Novel High
Nisch Hom Novel Mild
Nptn Hom Novel Severe
Ocm Hom Known Severe
Odf3l2 Hom Novel Mild
Otoa Hom Known Severe
Phf6 Het Novel High
Ppm1a Hom Novel High
Sema3f Hom Novel Low
Slc4a10 Hom Novel Mild
Slc5a5 Hom Novel Severe
Spns2 Hom Novel Severe
Srrm4 Hom Known Mild
Tmem30b Hom Novel Severe
Tmtc4 Hom Novel Severe
Tox Hom Novel Severe
Tprn Hom Known Severe
Tram2 Hom Novel Mild
Ube2b Het Novel Mild
Ube2g1 Hom Novel Mild
Ush1c Hom Known Severe
Vti1a Hom Novel Mild
Wdtc1 Hom Novel High
Zcchc14 Hom Novel Low
Zfp719 Hom Novel Severe

Vignettes

Novel, mild hearing loss

Ap3s1tm1b(EUCOMM)Hmgu

Known, severe hearing loss

Elmod1tm1b(EUCOMM)Hmgu

Novel, high-frequency hearing loss

Ccdc88ctm1b(KOMP)Mbp

Novel, severe hearing loss

Zfp719tm1b(EUCOMM)Wtsi

Phenotypes distribution

hearing IKMC/IMPC related publications