An international team of scientists led by the LKS Faculty of Medicine, University of Hong Kong (HKUMed) has discovered the underlying cause of deafness caused by swelling of the chambers in the inner ear.
Using a mouse model of a human congenital disorder that appears deafnessthe researchers identified two master genes controlling hearing function, which opens a new avenue for the diagnosis of deafness and balance problems, and possibly their consequences stem cells in other tissues and syndromes. This exciting progress is described in their paper published in the journal, Procedures of the National Academy of Sciences.
Hearing and balance require a functioning inner ear, which houses the sensory organs, and a system that mediates the transmission of sound through a fluid-filled chamber called the endolymphatic system, which consists of the endolymphatic duct and sac. These tissues help control the amount of ions in the fluid (called endolymph) in the inner ear and thereby allow sound and balance signals to be transmitted to the nerves and brain.
Damage to the endolymphatic system is a common cause of deafness. The endolymph is essential for hearing function. Dysfunction of this fluid results in swelling of the endolymphatic sac (called hydrops), causing hearing loss, dizziness, fullness of hearing, and pain.
HKUMed scientists, leading an international research team, have generated and studied mouse models of a human condition called campomelic dysplasia (CD), a syndrome characterized in part by deafness of unknown etiology.
The team found that the underlying cause of deafness is a deficiency of two main regulatory factors called SOX9 and SOX10 (collectively referred to as SOXE genes). These factors were found to orchestrate the production of stem cells in inner ear development.
When these SOXE genes are deficient, the result is an insufficient supply of mature cells responsible for proper ionic composition of the endolymph and a functioning endolymphatic system. As a result, the chambers of the inner ear swell, causing deafness.
Human hearing loss leads to physical disabilities and causes problems in education, work and social life. It is estimated that one in ten people will experience hearing loss by 2050 and one to three newborns per thousand will be hearing impaired, with 50% due to genetic causes. A disturbance affecting the ionic composition in the endolymph is the most common cause of deafness.
Because SOXE genes are master controllers of many other genes, another effect of the study is that it provides a rich resource for the discovery of other candidate genes for congenital deafness or other disease genes regulated by the SOXE factors. The source can be a guide to the diagnosis of deafness and balance problems. Since SOXE genes play many roles in development and in stem cells, the principles found may apply to effects on stem cells in general in other tissues and disease states.
Professor Kathryn Cheah Song Eng, Jimmy and Emily Tang Professor of Molecular Genetics and Chair Professor of Biochemistry, School of Biomedical Sciences, HKUMed, who led the study, said: “Being deaf can have profound psychological and social impact on the affected person. Discovering the master controllers of the inner ear sound conduction system provides insight into the disease mechanism that will help develop a treatment that will have a huge impact on the many people with hearing loss.”
Dr. Brian Chung Hon-yin, clinical geneticist/clinical associate professor, Department of Pediatrics and Adolescent Medicine, School of Clinical Medicine, HKUMed, commented: “Congenital deafness is an important indication for referral in clinical genetics. Patients with both syndromic and nonsyndromic Syndromic hearing loss is common. Despite recent studies suggesting a genetic diagnosis in up to 50% of patients, the underlying pathophysiology remains complex and poorly understood.
“This exciting work shows compelling evidence of the collaboration between SOX9 and SOX10 in controlling the development of the endolymphatic system. It sheds light on the future direction for research by clinical geneticists and scientists in deciphering other disorders of the to belong constraint.”
Irene YY Szeto et al, SOX9 and SOX10 regulate fluid homeostasis in the inner ear for hearing through independent and cooperative mechanisms, Procedures of the National Academy of Sciences (2022). DOI: 10.1073/pnas.2122121119
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