The IMPC is hunting unknown genes responsible for hearing loss by screening knockout mice. Worldwide, 360 million people live with mild to profound hearing loss. Notably, 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.
- Press releases: EMBL-EBI | MRC | IMPC
- Nature Communications (released 12/10/2017)
- Supplementary Material
Approach
In order to identify the function of genes, the consortium uses a series of 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:
- Auditory Brain Stem Response NINGLA v2 , ICSLA v2 , IMPC v1 , IMPC v1 , RBRCLA v2 , IMPC v2 , IMPC v2 , IMPC v1 , IMPC v1 , BCMLA v2 , IMPC v2 , IMPC v2 , IMPC v2 , IMPC v1 , IMPC v2 , IMPC v1 , IMPC v2 , IMPC v1 , IMPC v1 , RBRCIP v2 , IMPC v2 , IMPC v2 , IMPC v2 , KMPCLA v2
- Combined SHIRPA and Dysmorphology JAXLA v1 , UCDIP v3 , IMPC v2 , IMPC v3 , IMPC v1 , MGP v1 , JAXLA v2 , IMPC v1 , IMPC v3 , BCM v1 , BCMIP v3 , KMPCLA v3 , TCPLA v3 , IMPC v3 , IMPC v2 , IMPC v3 , IMPC v1 , NINGLA v2 , IMPC v1 , IMPC v2 , IMPC v3 , UCDLA v3 , IMPC v1 , IMPC v1 , KMPCIP v3 , IMPC v3 , IMPC v3 , IMPC v2 , IMPC v2 , HRWLLA v3 , JAXLA v3 , IMPC v2 , IMPC v2 , ICSLA v3 , IMPC v3 , RBRCLA v3 , HRWLIP v3 , BCMLA v3 , IMPC v1 , TCPIP v3 , IMPC v3
IMPC Deafness Publication
Hearing loss investigated in 3,006 knockout mouse lines
- 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
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
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 |