Thesis
Deciphering deafness in Down syndrome: finding the otitis media gene
- Abstract:
-
Hearing impairment, particularly in children with Down syndrome (DS), can lead to isolation and developmental issues. The most common cause of hearing loss in children with DS is otitis media with effusion (OME). OME is defined as inflammation of the middle ear epithelial lining and the accumulation of fluid in the middle ear cavity, without the presence of a pathogen. The middle ear fluid impedes the passage of sound waves to the inner ear. OME is known to have a strong genetic component, and children with DS are particularly susceptible.
With the aid of a mapping panel of partial trisomy mouse models, it was found that mice carrying a duplication of the genes in the Dp5Tyb region demonstrate highly penetrant OME affecting one or both ears. The Dp5Tyb region only contains 12 protein coding genes, all of which have human chromosome 21 orthologues. The DS and deafness phenotypes of Dp5Tyb mice were investigated, and also the expression of the 12 genes in the middle ear environment. Single gene knockout mice for Dp5Tyb genes were crossed to Dp5Tyb or Dp3Tyb mice, thus restoring disomy of one gene in double mutant offspring. Analysis of these double mutants identified Dyrk1a as a key gene of interest. When Dyrk1a dosage was restored to two copies in a DS mouse the OME phenotype was rescued to wildtype levels. Investigations into how increased Dyrk1a dosage contributes to OME pathogenesis provided evidence that it impacts on a number of processes, including promoting TGF-β signalling and driving the differentiation of naïve CD4+ T cells into pro-inflammatory Th17 cells.
These studies suggest that the administration of DYRK1A inhibitors to Dp5Tyb mice could ameliorate the OME phenotype. The application of this to young children with DS could make a big difference to their speech and language development.
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Authors
Contributors
- Role:
- Supervisor
- Role:
- Supervisor
- Institution:
- University of Oxford
- Division:
- MSD
- Department:
- Physiology Anatomy & Genetics
- Role:
- Supervisor
- ORCID:
- 0000-0002-1141-6613
- Institution:
- University of Oxford
- Division:
- MSD
- Department:
- Biochemistry
- Role:
- Supervisor
- ORCID:
- 0000-0003-0951-3374
- Funder identifier:
- http://dx.doi.org/10.13039/501100000265
- Funding agency for:
- Southern, A
- Programme:
- Oxford-MRC Doctoral Training Programme
- DOI:
- Type of award:
- DPhil
- Level of award:
- Doctoral
- Awarding institution:
- University of Oxford
- Language:
-
English
- Keywords:
- Subjects:
- Deposit date:
-
2023-08-24
Terms of use
- Copyright holder:
- Southern, A
- Copyright date:
- 2022
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