Deafness and Inherited Hearing Loss
Deafness is the lack of functional sense of hearing in both ears. Loss of hearing can result from environmental or genetic causes and it can be temporary or permanent.
Environmental loss of hearing results from occupational noise, noise pollution, accidents, or intake of certain drugs. Inherited loss of hearing can be caused by mutations in any of over a hundred of genes known to affect hearing, and can affect various cells of the inner ear, the main hearing center.
The inner ear contains the organ of Corti, which has hair cells that are responsible for converting sounds to neuronal signals. These cells possess receptors responsive to mechanical movement, stereocilia, which are long, hair like-extensions. Stereocilia are surrounded by a liquid (endolymph) containing high concentration of potassium ions, while the main channels of the inner ear are filled with a liquid (perilymph) rich in sodium ions. Changes in pressure resulting from a sound stimulus, are passed through the perilymph and result in a mechanical distortion of the stereocilia. This induces transfer of potassium ions into the hair cells and stimulation of the neurons.
Hearing loss in the inherited cases of deafness can be syndromic or non-syndromic. Deafness or profound hearing loss is often associated with other genetic syndromes (for example Waardenburg or Pendred syndrome). These account for about 30% of all inherited hearing loss. In these patients the mutations can affect the inner ear (sensineuronal) or sound transmission through the outer and middle ear (conductive), or can affect both. The remainder of the inherited cases are nonsyndromic (patients do not exhibit any other symptoms except for the loss of hearing).
Knowledge about the role of particular genes and general metabolic and signal transduction pathways in the cells of the inner ear is very limited. As a result, the genes causing the non-syndromic hearing loss are divided into artificial groups based on the mode of transmission: autosomal recessive (77%), autosomal dominant (22%), X chromosome linked (around 1%) and mitochondrial (less than 1%).
Hearing loss in case of recessive mutations is usually congenital as the patient receives two copies of the same mutation from the parents, resulting in complete absence of a functional protein. In contrast, the dominant mutations can be transmitted by only one parent, resulting in one good and one bad copy of the gene (two copies can be obtained as well if both parents are affected and have the same mutation in the same gene). Such patients usually exhibit progressive hearing loss, as initially there is some functional protein.
Defects that result in deafness or progressive hearing loss can affect different parts of the inner ear, hair cells, non-sensory cells, and the tectorial membrane.
A large number of mutations causing deafness affect the proteins essential for proper function of the organ of Corti. The changes found in the hair cells affect mainly the motor proteins, such as myosins (myosin 7A, 6 and 15), or interacting with actin filaments (espin), but also potassium (KCNQ4) and calcium ion transporters, cadherins (vezatin and harmonin), and a transcription factor (POU4F3). This results in the changed structure of the hair cells, loss of their mechanical ability to stretch and distort, and affects ion-dependent signalling. Another mechanical part of the inner ear is the tectorial membrane. This gelatinous structure composed of proteins of the extracellular matrix is bound to the stereocilia of some hair cells. Mutations that affect it are found mainly in the proteins of the extracellular matrix (collagen 11 or tectoin). These changes are thought to affect the mechanical and structural properties of the membrane.
The non-sensory cells are an important part of the inner ear, forming tight barriers preventing mixing of the potassium and sodium rich liquids, and supporting the hair cells. The mutations in these cells affect mainly the gap and tight junction proteins (connexin 26, 30, 31 and claudin 14) responsible for cell-to-cell contact, but also ion transporters (calcium and potassium), and a transcription factor (POU3F4).
Other genes that are mutated have not been yet localised to a particular cell type. Moreover, it has been suggested that there are certain genes (modifiers) increasing the susceptibility of age-related or noise-induced hearing loss. This could also explain why the mutations in the same gene result in very different severity of hearing loss.
See also Genetic disorders.
Avraham, Karen B. "Modifying with Mitochondria." Nature Genetics (February 2001): 136-137.
Petit, Christine, Jacqueline Levilliers, and Jean-Pierre Hardelin. "Molecular Genetics of Hearing Loss." Annual Review of Economics and Human Genetics. (2001): 589.646.
Steel, Karen P., and Corne J. Kros, "A Genetic Approach to Understanding Auditory Function." Nature Genetics (February 2001): 143-149.
Atlantic Coast Ear Specialists, P.C. "Anatomical Tour Of The Ear." [cited January 22, 2003] <http://www.earaces.com/anatomy.htm>.
Van Camp, Guy, and Richard Smith. The Hereditary Hearing Loss Homepage [cited January 22, 2003]. <http://www.uia.ac.be/dnalab/hhh>.