Advances in cochlear implantation for hereditary deafness caused by common mutations in deafness genes

The pathogenic factors of deafness are complex;more than 50%of cases are caused by genetic factors.Between 75%and 80%of cases of hereditary hearing impairment are autosomal recessive,15%to 25%are autosomal dominant,and 1%to 2%are mitochondrial or X-linked.Cochlea implantation is the main method for treating severe and extremely severe bilateral sensorineural deafness and it is widely used in clinical treatment.As clinical cases of cochlea implantation accumulate,differences in the efficacy of implantation in individuals are emerging and attracting attention.In addition to residual hearing level,implantation age,and other factors,gene mutation is an important factor influencing postoperative rehabilitation in patients.With continuous progress in genetic testing technology for deafness,genetic diagnosis has become an important tool in preoperative evaluation and postoperative effect prediction in patients undergoing cochlear implantation.This article reviews the current status and future development of cochlear implantation in the treatment of hereditary deafness resulting from mutations in common deafness-causing genes.

APPLICATION OF GENETIC DEAFNESS GENE CHIP FOR DETECTION OF GENE MUTATION OF DEAFNESS IN PREGNANT WOMEN

Objective The study is to identify the carrier rate of common deafness mutation in Chinese pregnant women via detecting deafness gene mutations with gene chip. Methods The pregnant women in obstetric clinic without hearing impairment and hearing disorders family history were selected. The informed consent was signed. Peripheral blood was taken to extract genom- ic DNA. Application of genetic deafness gene chip for detecting 9 mutational hot spot of the most common 4 Chinese deafness genes, namely GJB2 （35delG, 176del16bp, 235delC, 299delAT）, GJB3 （C538T） ,SLC26A4 （ IVS72A〉G, A2168G） and mito- chondrial DNA 12S rRNA （A1555G, C1494T） . Further genetic testing were provided to the spouses and newborns of the screened carriers. Results Peripheral blood of 430 pregnant women were detected, detection of deafness gene mutation carri- ers in 24 cases（4.2%）, including 13 cases of the GJB2 heterozygous mutation, 3 cases of SLC26A4 heterozygous mutation, 1 cases of GJB3 heterozygous mutation, and 1 case of mitochondrial 12S rRNA mutation. 18 spouses and 17 newborns took further genetic tests, and 6 newborns inherited the mutation from their mother. Conclusion The common deafness genes muta- tion has a high carrier rate in pregnant women group, 235delC and IVS7-2A〉G heterozygous mutations are common.

Advantages of a miniature pig model in research on human hereditary hearing loss

In medical laboratory animals, the pig is the closest species to human in evolution, except for primates. As an animal model, the pig is highly concerned by many scientists, including comparative biology, developmental biology, medical genetics. Rodents as animal model for human hearing defects has are poor producibility and reliability, due to differences in anatomical structure, evolutionary rate and metabolic rate, but these happens to be the advantages of the pig model. In this paper, we will summarize the application of miniature pig in the study of human hereditary deafness.

<i>GJB2</i>Gene Related Nonsyndromic Hearing Loss in Mazandaran Province, North of Iran

Introduction: Congenital hearing loss is the most common sensory deficit in the world and mutations in GJB2 gene are the most common cause of deafness in many populations. Frequency of GJB2 mutations is estimated about 16% in Iran and varies among different provinces with a decreasing trend from north to south. The aim of this study was to investigate the frequency of GJB2 mutations in Mazandaran province, north of Iran, among non-syndromic hearing loss patients. Methods: 262 patients from 204 families participated in this study. After genomic DNA extraction, GJB2 gene analysis was carried out using DNA sequencing of both coding and non-coding regions by ABI 3130XL genetic analyzer. Results: 30.15% of all subjects showed mutations in GJB2 gene. Four mutations, including c.35delG (Gly12Valfs*), IVSI-1 + 1G > A, c.95G > A (Arg32His) and c.224 G > A (Arg75Gln) comprises 69.89% of all mutations in this study c.35delG and IVSI-1 were the most common mutations among patients respectively. Codon 75 mutation (c.224G > A. p: Arg75Gln) with autosomal dominant inheritance was seen in 7 cases from 3 families. 22 patients showed only one mutation in GJB2 gene and in 126 (48.09%) individuals, parents had a consanguineous marriage. Discussion: Frequency of GJB2 gene related hearing loss among patients was higher than average (16%) in this province. This study also showed a dominant inheritance pattern of GJB2 gene in this area. Consanguineous marriage also showed highly frequent among parents. More investigation needs to clarify cause of hearing loss in those 22 patients with one mutation in GJB2 gene, either two gene inheritance or another gene may be responsible for hearing loss.

The plasma membrane calcium pump in the hearing process:physiology and pathology

Mammalian cells express four different plasma membrane Ca2+ ATPases.Two of them(PMCA1 and PMCA4) are expressed ubiquitously,and are considered housekeeping isoforms.Two(PMCA2 and PMCA4) have tissue restricted distribution.They are abundantly expressed in the brain and in nervous tissue-derived cell types.The primary transcripts of all PMCAs undergo alternative splicing,generating a large number of additional isoforms.Splicing occurs at site A,in the N-terminal moiety of the pump,and at site C,within the C-terminal calmodulin binding domain:The pumps are canonical targets of calmodulin stimu-lation.The site C insertion leads to a truncation of the pump about 50 residues short of the original C-terminal.One of the pumps(PMCA2) has special properties:It displays high activity even in the absence of the natural activator calmodulin,and has a particularly complex pattern of alternative splicing at both sites A and C.A variant of the PMCA2 pump containing an insert at site A and truncated C-terminally is the resident isoform of the pump in the stereocilia of hair cells of the inner ear.It exports Ca2+to the endolymph that bathes the stereocilia less efficiently than the full length,non-inserted PMCA2 pump.The proper functioning of hair cells demands the precise maintenance of the Ca2+balance between hair cells and the endolymph. Disturbances in the balance affect the process of mechano-electrical transduction,which depends on the ability of the stereo-ciliar bundle to deflect in response to sound waves.The tip links that organize the bundle are formed by the Ca2+binding pro-tein cadherin 23 and by protocadherin 15:Disturbances of the Ca2+binding by cadherin 23 and/or of the ability of the PMCA2 variant of the stereocilia to export Ca2+to the endolymph generate hearing loss phenotypes.Such phenotypes have now been described in mice and humans.In some cases they are linked to mutations of both cadherin 23 and the PMCA2 pump,but in other cases they may be generated by mutations of particular severity in only one of the two proteins.The PMCA2 defect that leads to deafness has now been analyzed molecularly:It affects the long range,unstimulated ability of PMCA2 to export Ca2+.

Etiology of newborn hearing impairment in Guangdong province: 10-year experience with screening, diagnosis, and follow-up

Background Hearing impairment is one of the most common birth defects in children.Universal newborn hearing screenings have been performed for 19 years in Guangdong province,China.A screening/diagnosis/intervention system has gradually been put in place.Over the past 10 years,a relatively complete data management system had been established.In the present study,an etiological analysis of newborn cases that failed the initial and follow-up screenings was performed.Methods The nature and degree of hearing impairment in newborns were confirmed by a set of procedures performed at the time of initial hearing screening,rescreening and final hearing diagnosis.Then,multiple examinations were performed to explore the associated etiology.Results Over a period of 10 years,720 children were diagnosed with newborn hearing loss.Among these children,445 (61.81%) children had a clearly identified cause,which included genetic factor(s) (30.56%),secretory otitis media (13.30%),maternal rubella virus infection during pregnancy (5.83%),inner ear malformations (4.86%),maternal human cytomegalovirus infection during pregnancy (2.92%),malformation of the middle ear ossicular chain (2.50%) and auditory neuropathy (1.81%).In addition,275 cases of sensorineural hearing loss of unknown etiology accounted for 38.19% of the children surveyed.Conclusions Long-term follow-up is needed to detect delayed hearing impairment and auditory development in children.The need for long-term follow-up should be taken into account when designing an intervention strategy.Furthermore,the use of the deafness gene chip should further elucidate the etiology of neonatal hearing impairment.