Deafness-related Genes Research Articles

Mutational analysis of the SLC26A4 gene in Chinese sporadic nonsyndromic hearing-impaired children

ObjectiveTo investigate the mutations of SLC26A4 gene and the relevant phenotype in Chinese sporadic nonsyndromic hearing-impaired children. Methods195 Chinese sporadic nonsyndromic hearing-impaired children were subjected to microarray-based mutation detection for 9 hot spot mutations in four of the most common deafness-related genes (GJB2, SLC26A4, GJB3, and 12s rRNA). Subsequently, twenty-one patients with one SLC26A4 mutation detected by microarray were subjected to sequencing analysis of the whole SLC26A4 coding region and the splice sites in order to identify the second mutant allele. The inner ear malformation and hearing loss level were compared among different genotypes. ResultsThe incidence of genetic mutations was found to be 43.59% (85/195) in this patient group using CapitalBio Deafness Gene Mutation Detection Array Kit. A total of 34 children (17.44%) were found carrying the mutant SLC26A4 sequences. Thirteen (6.67%) children carried two mutant alleles of SLC26A4 and 21 (10.77%) children carried one mutant allele of SLC26A4. After the application of subsequent sequencing analysis, 13 mutational variants including 4 novel variants, two missense (p.D661G, p.N457D), one splice site mutation (IVS15+1G>A) and one frameshift mutation (624_632del9insACTTGGC), were identified in SLC26A4 gene in 15 of the 21 previously monoallelic patients. No second mutation was identified in the remaining 6 children. Biallelic mutations of SLC26A4 were identified in 20 of 21 children with enlarged vestibular aqueduct. ConclusionsOur results demonstrated that genetic factors were important causes for sporadic nonsyndromic hearing loss in Chinese pediatric cases. Mutation of SLC26A4 is one of the major genetic causes in nonsyndromic hearing loss with inner ear malformation. IVS7-2A>G, 2168A>G and 1229C>T were the most frequent mutations identified in our studies. The combination of microarray testing and sequencing analysis is a useful and high-throughput method for the diagnosis of genetic hearing loss.

Common molecular etiologies are rare in nonsyndromic Tibetan Chinese patients with hearing impairment.

BackgroundThirty thousand infants are born every year with congenital hearing impairment in mainland China. Racial and regional factors are important in clinical diagnosis of genetic deafness. However, molecular etiology of hearing impairment in the Tibetan Chinese population living in the Tibetan Plateau has not been investigated. To provide appropriate genetic testing and counseling to Tibetan families, we investigated molecular etiology of nonsyndromic deafness in this population.MethodsA total of 114 unrelated deaf Tibetan children from the Tibet Autonomous Region were enrolled. Five prominent deafness-related genes, GJB2, SLC26A4, GJB6, POU3F4, and mtDNA 12S rRNA, were analyzed. Inner ear development was evaluated by temporal CT. A total of 106 Tibetan hearing normal individuals were included as genetic controls. For radiological comparison, 120 patients, mainly of Han ethnicity, with sensorineural hearing loss were analyzed by temporal CT.ResultsNone of the Tibetan patients carried diallelic GJB2 or SLC26A4 mutations. Two patients with a history of aminoglycoside usage carried homogeneous mtDNA 12S rRNA A1555G mutation. Two controls were homozygous for 12S rRNA A1555G. There were no mutations in GJB6 or POU3F4. A diagnosis of inner ear malformation was made in 20.18% of the Tibetan patients and 21.67% of the Han deaf group. Enlarged vestibular aqueduct, the most common inner ear deformity, was not found in theTibetan patients, but was seen in 18.33% of the Han patients. Common molecular etiologies, GJB2 and SLC26A4 mutations, were rare in the Tibetan Chinese deaf population.ConclusionThe mutation spectrum of hearing loss differs significantly between Chinese Tibetan patients and Han patients. The incidence of inner ear malformation in Tibetans is almost as high as that in Han deaf patients, but the types of malformation vary greatly. Hypoxia and special environment in plateau may be one cause of developmental inner ear deformity in this population.

Preliminary studies on differential expression of auditory functional genes in the brain after repeated blast exposures

The mechanisms of central auditory processing involved in auditory/vestibular injuries and subsequent tinnitus and hearing loss in Active Duty servicemembers exposed to blast are not currently known. We analyzed the expression of hearing-related genes in different regions of the brain 6 h after repeated blast exposures in mice. Preliminary data showed that the expression of the deafness-related genes otoferlin and otoancorin was significantly changed in the hippocampus after blast exposures. Differential expression of cadherin and protocadherin genes, which are involved in hearing impairment, was observed in the hippocampus, cerebellum, frontal cortex, and midbrain after repeated blasts. A series of calcium-signaling genes that are known to be involved in auditory signal processing were also found to be significantly altered after repeated blast exposures. The hippocampus and midbrain showed significant increase in the gene expression of hearing loss-related antioxidant enzymes. Histopathology of the auditory cortex showed more significant injury in the inner layer compared to the outer layer. In summary, mice exposed to repeated blasts showed injury to the auditory cortex and significant alterations in multiple genes in the brain known to be involved in age- or noise-induced hearing impairment.

Microarray-based mutation detection of pediatric sporadic nonsyndromic hearing loss in China

Objective To investigate the molecular etiologic causes of sporadic nonsyndromic hearing loss in Chinese children. Methods 179 sporadic nonsyndromic hearing loss children were subjected to microarray-based mutation detection for nine hot spot mutations in four of the most common deafness-related genes, including GJB2, SLC26A4, GJB3, and 12s rRNA. Results The incidence of positive genetic errors was 43.58% with the current set of target genes in sporadic nonsyndromic hearing loss children. Among them, 25.14% of cases had genetic defects in GJB2, 16.76% of cases had pathogenic mutations in SLC26A4, 1.12% of cases were caused by 12s rRNA mutations, and GJB3 mutation was detected in 0.56% of this group of patients. Conclusions Our results demonstrated that genetic factors were important causes for sporadic nonsyndromic hearing loss in Chinese pediatric cases. Mutations of GJB2 and SLC26A4 are two major genetic causes, whereas mutations of GJB3 and 12s rRNA result in the development of hearing loss in a small percentage of sporadic nonsyndromic hearing loss cases. Microarray testing is a helpful and instrumental screening method in the diagnosis of genetic hearing loss.

Molecular epidemiological analysis of mitochondrial DNA12SrRNA A1555G, GJB2, and SLC26A4 mutations in sporadic outpatients with nonsyndromic sensorineural hearing loss in China

Conclusion: GJB2 mutation was frequent in sporadic outpatients and its mutation frequency was significant higher in the prelingual group than in the postlingual group, whereas the mutation of mtDNA A1555G and SLC26A4 was very rare in Chinese sporadic outpatients with nonsyndromic sensorineural hearing loss (NSHL). Standard and comprehensive inclusion and grouping criteria are necessary for epidemiological studies of deafness-related gene mutations. Objectives: This study aimed to examine the mutations of the three common deafness genes GJB2, SLC26A4, and mtDNA A1555G in Chinese sporadic outpatients with NSHL and to discuss the factors that influence the detection accuracy of mutation frequencies. Methods: A total of 473 sporadic NSHL patients without any type of inner ear malformation, including both prelingual and postlingual groups were enrolled in this study. Three genes of mtDNA A1555G, GJB2, and SLC26A4 were screened for mutation in our study cohort. A chi-square test was performed to compare mutation frequencies between prelingual and postlingual groups. Results: The mutation frequencies of MtDNA A1555G, GJB2, and SLC26A4 were 1.63%, 13.63%, and 0%, respectively, in our study cohort. The mutational hot spot of GJB2 was c.235delC, whose allele frequency was 12.68% in sporadic outpatients. Mutation frequency of GJB2 in the prelingual group was significantly higher than in the postlingual group (p < 0.05).

SLC26A4 c.919-2A>G varies among Chinese ethnic groups as a cause of hearing loss

PurposeMutations in the SLC26A4 gene are second only to GJB2 mutations as a currently identifiable genetic cause of sensorineural hearing loss. In most areas of China, genetic testing for sensorineural hearing loss is unavailable because of limited knowledge of the mutation spectrum. Although SLC26A4 c.919-2A>G (IVS7–2A>G) is a common mutation among some Asian populations, the mutation prevalence among various ethnic groups within China has not been studied. MethodsDNA specimens from 3271 subjects with moderate to profound sensorineural hearing loss from 27 regions of China were genotyped for the c.919-2A>G mutation by polymerase chain reaction/restriction-fragment-length polymorphism. Normal hearing controls from Han (n = 185) and Uigur (n = 152) populations were also tested. ResultsOverall, 408 subjects with sensorineural hearing loss (12.5%) carried at least one c.919-2A>G allele, with 158 (4.8%) homozygotes and 250 (7.6%) heterozygotes. Within the subpopulations examined, the rate varies from 0% to 12.2% for c.919-2A>G homozygotes and from 0% to 17.6% for heterozygotes. Based on this cohort, Chinese subjects with sensorineural hearing loss seem to have a relatively higher c.919-2A>G frequency than that of other Asian populations. ConclusionThese results demonstrate that a simple and efficient genetic test for the c.919-2A>G mutation alone would identify the molecular cause in up to 8–12% of individuals with sensorineural hearing loss in a few eastern and central regions of China. Those who are negative for the c.919-2A>G mutation would be candidates for further mutational analysis of SLC26A4 or other deafness-related genes. This would greatly improve genetic diagnosis and counseling for a huge number of Chinese individuals and family members with sensorineural hearing loss in China, and many more ethnic Chinese in other countries, which might be up to one million.

The prevalence of the 235delC GJB2 mutation in a Chinese deaf population

PurposeMutations in the GJB2 gene are the most frequently found mutations in patients with nonsyndromic hearing impairment in populations studied to date. However, the prevalence of mutations varies among different ethnic groups. In most areas of China, genetic testing for nonsyndromic hearing impairment is currently not available because of the lack of information regarding the molecular cause of nonsyndromic hearing impairment. The purpose of this study is to determine the prevalence of a common GJB2 mutation, 235delC, in Chinese deaf children. MethodsWe collected DNA specimens from 3004 patients with nonsyndromic hearing impairment from 26 regions of China; 368 Han Chinese and 98 Uigur controls, and screened for the 235delC mutation. The coding exon of the GJB2 gene was polymerase chain reaction amplified, followed by restriction enzyme digestion with ApaI and analysis by agarose gel. ResultsOverall, 488 patients (16.3%) were determined to carry at least one 235delC mutant allele, with 233 (7.8%) homozygotes and 255 (8.5%) heterozygotes. Therefore, within the subpopulations examined, the frequency varies from 0% to 14.7% for 235delC homozygotes and from 1.7% to 16.1% for heterozygotes. On the basis of this survey of the patient cohort as stated, Chinese patients with nonsyndromic hearing impairment appear to have a relatively higher 235delC frequency than that of other Asian populations. ConclusionThese results demonstrate that an easy and fast genetic testing method for this well-known GJB2 gene mutation can be made available for at least 2 million Chinese patients and family members with nonsyndromic hearing impairment. By screening for the common GJB2 235delC mutation, the molecular cause in as high as 15% of patients with nonsyndromic hearing impairment in certain regions of China can be identified. In addition, patients who are negative for the 235delC mutation would be candidates for further mutational analysis of GJB2 or other deafness-related genes.

Mouse models to study inner ear development and hereditary hearing loss

Hereditary sensorineural hearing loss, derived from inner ear defects, is the most common hereditary disability with a prevalence of 1 in 1,000 children, although it can be present in up to 15% of births in isolated communities. The mouse serves as an ideal animal model to identify new deafness-related genes and to study their roles in vivo. This review describes mouse models for genes that have been linked with hearing impairment (HI) in humans. Mutations in several groups of genes have been linked with HI in both mice and humans. Mutant mice have been instrumental in elucidating the function and mechanisms of the inner ear. For example, the roles of collagens and tectorins in the tectorial membrane, as well as the necessity of intact links between the hair cell projections, stereocilia and kinocilia, have been discovered in mice. Accurate endolymph composition and the proteins which participate in its production were found to be crucial for inner ear function, as well as several motor proteins such as prestin and myosins. Two systematic projects, KOMP and EUCOMM, which are currently being carried out to create knock-out and conditional mutants for every gene in the mouse genome, promise that many additional deafness-related genes will be identified in the next years, providing models for all forms of human deafness.

Genomic analysis of a heterogeneous Mendelian phenotype: multiple novel alleles for inherited hearing loss in the Palestinian population

Recessively inherited phenotypes are frequent in the Palestinian population, as the result of a historical tradition of marriages within extended kindreds, particularly in isolated villages. In order to characterise the genetics of inherited hearing loss in this population, we worked with West Bank schools for the deaf to identify children with prelingual, bilateral, severe to profound hearing loss not attributable to infection, trauma or other known environmental exposure. Of 156 families enrolled, hearing loss in 17 families (11 per cent) was due to mutations in GJB2 (connexin 26), a smaller fraction of GJB2-associated deafness than in other populations. In order to estimate how many different genes might be responsible for hearing loss in this population, we evaluated ten families for linkage to all 36 known human autosomal deafness-related genes, fully sequencing hearing-related genes at any linked sites in informative relatives. Four families harboured four novel alleles of TMPRSS3 (988ΔA = 352stop), otoancorin (1067A >T = D356V) and pendrin (716T > A = V239D and 1001G > T = 346stop). In each family, all affected individuals were homozygous for the critical mutation. Each allele was specific to one or a few families in the cohort; none were widespread. Since epidemiological tests of association of mutations with deafness were not feasible for such rare alleles, we used functional and bioinformatics approaches to evaluate their consequences. In six other families, hearing loss was not linked to any known gene, suggesting that these families harbour novel genes responsible for this phenotype. We conclude that inherited hearing loss is highly heterogeneous in this population, with most extended families acting as genetic isolates in this context. We also conclude that the same genes are responsible for hearing loss in this population as elsewhere, so that gene discovery in these families informs the genetics of hearing loss worldwide.