Deafness is one of the most common diseases that afflict human beings. The World Health Organization estimates that 250 million people worldwide suffer from moderate hearing loss or more, and the second national sample survey of people with disabilities in 2006 showed that the total number of people with various types of disabilities in China was 82.96 million, of which 27.8 million had hearing disabilities, accounting for the highest number of all types of disabilities, and 20,000 to 30,000 deaf children are added every year.
In 1992, a literature report on the genes responsible for deafness – hereditary deafness – became a milestone in the study of hereditary deafness. It was hypothesized that more than half of congenital deafness is related to genetic factors, and most of the genetic deafness is severe or very severe sensorineural deafness, for which cochlear implantation is the most effective treatment and rehabilitation method. The efficacy of CI varies in hereditary deafness depending on the causative genes. Pre-operative CI can initially predict the efficacy of CI through deafness genetic testing to clarify the molecular pathogenesis of deafness and to select a treatment plan in a targeted manner.
Efficacy of cochlear implantation in patients with genetic deafness
At present, the number of CI surgeries worldwide has exceeded 400,000, and China has been carrying out polysomnography CI since 1995, and has completed more than 40,000 CI surgeries. The Department of Otolaryngology-Head and Neck Surgery of the PLA General Hospital has performed CI since the beginning of 1998 and has completed 2534 surgeries in this department since then.
Blood samples of 1123 patients who underwent CI at this hospital from June 2012 to June 2015 were collected, and the age of patients with CI ranged from 9 months to 75 years old, with an average of 6.5 years. The above patients were tested for mutations in the key causative genes GJB2 gene, SLC26A4 (PDS) gene mutation, mitochondrial DNA A1555G mutation gene and GJB3 gene mutation, and it was found that GJB2 mutation was the main causative factor in CI population, with a detection rate of about 26%; followed by SLC26A4 mutation, with a detection rate of 17.1%; mitochondrial DNA A1555G mutation, with a detection rate of about 0.5%; and GJB3 mutation was less common.
The outcome of post-CI rehabilitation of deafness due to different genetic factors varies greatly. In this paper, by reviewing the outcome of these patients after CI implantation and reviewing the relevant literature, the molecular pathogenesis of known genetic deafness and post-CI outcome are summarized as follows.
The GJB2 gene encodes the gap junction protein Cx26. The GJB2 gene was cloned in 1993 and is localized at 13 q11-12 with a full-length DNA of 4804 bp and a coding region of 678 bp. The gene was named DFNB1 because it was the first gene identified to cause autosomal recessive inherited deafness, and mutations in this gene are one of the major causes of nonsyndromic deafness .
Cx26 encoded by the GJB2 gene forms an integral gap junction channel with the gap junction protein of adjacent cells. This channel plays an important role in signaling and substance exchange, and is an important channel for the intercellular conversion of electrolytes (especially potassium ions), second messengers and metabolites, and the circulation of potassium ions in inner ear hair cells and lymphatic fluid in the cochlea is regulated by the above gap junction protein channel. Potassium ions enter the vascular stripe through the gap junction and are released by intermediate cells into the vascular stripe gap, where they return to the endolymph.
Cx26 is highly expressed in human cochlear hair cells, suggesting that mutations in the GJB2 gene are closely associated with deafness. The deafness may be caused by mutations in the coding region of the GJB2 gene that result in code-shifting mutations during protein translation, producing nonfunctional proteins that affect the structure of the gap junction protein and thus the normal opening and closing of the channel.
Due to the abnormality of the connecting channel, the circulation of potassium ions back into the endolymphatic fluid is affected and the concentration is abnormally changed, and reaching a certain concentration will lead to potassium toxicity in hair cells, which leads to sensorineural deafness, and most people exhibit congenital deafness. patients with GJB2-associated deafness have normal auditory nerve terminals and sufficient ganglion cell counts, and therefore, such patients are well suited for CI surgery, and the prognosis is satisfactory.
SLC26A4(PDS) gene
The large vestibularaqueduct (LVA) is the most common congenital malformation of the inner ear, resulting in autosomal recessive non-syndromic hearingloss (NSHL) deafness, and is closely related to mutations in the SLC26A4 gene. The SLC26A4 gene is located at 7q31, and the SLC26A4 gene that causes Pendred syndrome is localized in the same region as DFNB4, but DFNB4 deafness has temporal bone malformation and is not associated with thyroid abnormalities.
The SLC26A4 gene contains 21 exons with an open reading frame of 2343 bp, and mutation sites are distributed on all exons except exon 20. The mutations include missense mutations, nonsense mutations, synonymous mutations, shift mutations and base deletions in large segments, most of which are missense mutations and can lead to protein truncation.
The mechanism of deafness may be due to the abnormal enlargement of the vestibular aqueduct which disturbs the endolymphatic circulation balance, and the hyperosmolar fluid from the endolymphatic sac flowing back into the cochlea causing damage to the auditory nerve epithelium, resulting in sensorineural deafness, as well as the dysfunction of endolymphatic sac reabsorption in the enlarged vestibular aqueduct, resulting in disruption of electrolyte balance, and the accumulation of endolymphatic metabolites also disturbing the cochlear hair cell function. Patients with large vestibular aqueduct syndrome are suitable for CI surgery because the auditory nerve ends are normal and there are sufficient ganglion cell counts.
Mitochondrial DNA A1555GIn 1993, Prezant et al. discovered that the molecular pathological basis of non-syndromic deafness caused by aminoglycosides was a point mutation in mitochondrial DNA 12SrRNAA1555G. Subsequently, pathogenic mutations related to mitochondria have been discovered continuously, and now more than 270 mitochondrial DNA mutations are known to be related to human diseases, and those related to deafness There are about 18 mitochondrial DNA mutations associated with deafness.
Mitochondrial inheritance is maternally inherited, and drug deafness is hotspotted by the mitochondrial DNA A1555G mutation, and specific populations can develop the disease by carrying this pathogenic mutation. Reports of CI in patients with severe/very severe deafness due to mitochondrial DNAA1555G mutation show that ototoxic drugs mainly damage cochlear hair cells, but have little effect on the cochlear nerve and posterior pathways, and that such patients have better results after CI.
OTOF gene
The OTOF gene encodes the otoferlin protein and is located on the short arm of chromosome 2 at 2p23.1. The OTOF gene can be isolated from the DFNB9 gene, which contains 101496 bp bases in its DNA sequence. The protein amino acid lengths were 1997, 1230, 1307, and 1230 amino acids, respectively.
otoferlin is a transmembrane protein containing a calcium-binding region, which plays an important role in cell membrane transport and signaling, and may act as a calcium sensor, affecting the cytosolic action of inner ear hair cell ribbon synapses and neurotransmitter transmission, especially on inner hair cells. Mutations in this gene can lead to prespeech profound deafness, an autosomal recessive non-syndromic hearing loss that may be accompanied by an auditory neuropathy early in the course of the disease. The lesion mainly involves the synapses and the cochlear nerve is not involved, so CI implantation is effective.
The CDH23 gene encodes calmodulin 23, which is located on chromosome 10 and localized at 10q21-22, and is expressed in cochlear hair cells and Reissner’s membrane. It is assumed that the role of CDH23 in hair cells is mainly to form hard cilia junctions and apical junctions, which transmit lymphatic mechanical pressure into ion channels and convert auditory mechanical stimuli into electrochemical signals to produce hearing. .
When the CDH23 gene mutation decreases cell adhesion, it affects the conduction function of ion channels and prevents the hearing response, leading to deafness. Mutations in this gene, which is involved in the development of lateral connections in the static cilia of hair cells, cause non-syndromic deafness in DFNB12 and USH1D. cochlear implantation has been shown to be effective.
The MYO6 gene encodes myosin 6 , which is associated with two motifs, DFNA22 and DFNB3 7. This gene is localized at chromosome 6q13 with 32 exons, and the full length of this gene is about 70 kb. MYO6 protein plays a membrane stabilizing role in tissues and is associated with the integrity of the hair cell cell membrane. This protein is expressed in the cytoplasm of hair cells. Mutations in this gene can lead to fusion of hair cell static cilia at the base, and pure mutations in the gene can lead to congenital very severe non-syndromic deafness. Cochlear implantation has been shown to be effective.
The MYO7A gene encodes myosin 7A, which has 49 exons and encodes 2215 amino acids. MYO7A genes encode non-traditional myosins, which are motor molecules that structurally contain conserved heads that move toward actin filaments. Their tails are highly convergent, limiting the tail to bind to different macromolecular structural substances and transport them to the corresponding actin filaments, thus fulfilling the function of transporting substances.
This protein is mostly expressed in the epithelial tissues of the inner ear and the retina. It is hypothesized that the shape of hair cell bundles depends on the functional unit composed of MYO7A, Harmoninb and CDH23 proteins. MYO7A protein transports Harmonin b along the actin nuclei of developing static cilia, and Harmoninb anchors CDH23 to static cilia microfilaments, and the interaction of the three ensures the cohesiveness of static cilia.
Mutations in MYO7A gene are associated with Usher syndrome (deaf-blindness syndrome) type 1B, autosomal recessive deafness DFNB2, and autosomal dominant deafness DFNA11. Cochlear implantation for deafness due to this gene mutation has been shown to be effective.