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.
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
- Auditory Brain Stem Response BCMLA v2 , RBRCLA v1 , KMPCLA v2 , ICSLA v2 , IMPC v1 , NINGLA v2 , IMPC v2
- Combined SHIRPA and Dysmorphology BCM v1 , MGP v1 , BCMLA v3 , KMPCIP v3 , NINGLA v2 , ICSLA v3 , HRWLIP v3 , TCPIP v3 , JAXLA v1 , IMPC v2 , IMPC v3 , UCDLA v3 , TCPLA v3 , UCDIP v3 , IMPC v1 , BCMIP v3 , JAXLA v3 , RBRCLA v1 , HRWLLA v3 , KMPCLA v3 , JAXLA v2
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
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
Sixty-seven deafness genes were identified:
|Gene symbol||Zygosity||Status||Hearing loss|