Researchers from Uppsala University have been able to document and visualise
hearing loss-associated genes in the human inner ear, in a unique
collaboration study between otosurgeons and geneticists. The findings
illustrate that discrete subcellular structures in the human organ of
hearing, the cochlea, are involved in the variation of risk of age-related
hearing loss in the population. The study is published in BMC Medicine.
Hearing loss is a potentially debilitating condition that affects more than
1.23 billion people worldwide. The most common form of hearing loss, which
represents 90% of all cases, is related to the degenerative effects of aging
on hearing, i.e., age-related hearing loss or presbycusis. However, the
molecular mechanisms that underlie the development of age-related hearing
loss and individual variation in risk are poorly elucidated.
In the current study, a unique collaboration was established between
otologists and geneticists at Uppsala University, which allowed for
functional follow-up studies of candidate genes from genome-wide association
studies (GWAS) using immunohistochemistry in the human cochlea.
“The cochlea, and in particular the hearing organ, the organ of Corti, is a
highly vulnerable structure that is difficult to analyse since it is
surrounded by the hardest bone in the body,” says Helge Rask-Andersen, MD
and Senior Professor at the Department of Surgical Sciences. “We have been
able to study some of the molecular components of human hearing that are
critical for the conversion of sound to nerve electric impulses.”
Genetic variants at 67 genomic regions were found to contribute to increased
risk of age-related hearing loss. Genome-wide association studies (GWAS) on
hearing-related traits were performed in the UK Biobank, which has half a
million participants from the United Kingdom. Genetic associations are
difficult to interpret by themselves and follow-up experiments are often
required before causal genes can be inferred.
“It is an amazing opportunity to be able to follow up our findings in human
cochlear samples, since there are molecular differences between the hearing
organ of humans and other mammals,” says Mathias Rask-Andersen, Associate
Professor at the Department of Immunology, Genetics and Pathology.
Candidate proteins from GWAS were visualised with immunofluorescent
antibodies and super-resolution structured illumination microscopy (SR-SIM)
by Dr Wei Liu, MD and Associate Professor at the Department of Surgical
Sciences. Several proteins were observed within the spiral ganglion, which
contains the neuronal cell bodies that innervate the hair cells in the organ
of Corti and carry neuronal impulses to the brain via the cochlear nerve.
The researchers could also visualise hearing loss-associated proteins in
discrete subcellular domains in the hair cells for the first time in humans,
such as TRIO and F-actin-binding protein (TRIOBP) in the hair tufts
(stereocilia) and LIM domain only protein 7 (LMO7) in the cuticular plate,
which is an actin-rich structure that anchors stereocilia to the cell body.
The stereocilia are the microscopic or nano-sized ‘hairs’ that protrude from
the hair cells of the organ of Corti. They respond to mechanical vibrations
from sounds that reach us and are transferred and amplified from the ear
drum to the inner ear by the small middle ear bones.
Taken together, the findings from the current study demonstrate that common
genetic variations associated with age-related hearing loss affect the
structures of the cochlea, in particular the neuronal processes of the
spiral ganglion, but also structures directly involved in the transduction
of mechanical stimuli to neuronal impulses. This knowledge may help to
better understand the biological mechanisms that lead to age-related hearing
loss and generate strategies for prevention such as novel pharmacological
treatments.
Reference:
Liu W, Johansson Å, Rask-Andersen H, Rask-Andersen M. A combined genome-wide
association and molecular study of age-related hearing loss in H. sapiens.
BMC Med. 2021;19(1):302.
DOI: 10.1186/s12916-021-02169-0