Nuclear and mitochondrial genes mutated in nonsyndromic impaired hearing

Department of Neurology, Krankenanstalt Rudolfstiftung, Vienna, Austria.
International Journal of Pediatric Otorhinolaryngology (Impact Factor: 1.19). 06/2005; 69(5):621-47. DOI: 10.1016/j.ijporl.2004.12.002
Source: PubMed


Half of the cases with congenital impaired hearing are hereditary (HIH). HIH may occur as part of a multisystem disease (syndromic HIH) or as disorder restricted to the ear and vestibular system (nonsyndromic HIH). Since nonsyndromic HIH is almost exclusively caused by cochlear defects, affected patients suffer from sensorineural hearing loss. One percent of the total human genes, i.e. 300-500, are estimated to cause syndromic and nonsyndromic HIH. Of these, approximately 120 genes have been cloned thus far, approximately 80 for syndromic HIH and 42 for nonsyndromic HIH. In the majority of the cases, HIH manifests before (prelingual), and rarely after (postlingual) development of speech. Prelingual, nonsyndromic HIH follows an autosomal recessive trait (75-80%), an autosomal dominant trait (10-20%), an X-chromosomal, recessive trait (1-5%), or is maternally inherited (0-20%). Postlingual nonsyndromic HIH usually follows an autosomal dominant trait. Of the 41 mutated genes that cause nonsyndromic HIH, 15 cause autosomal dominant HIH, 15 autosomal recessive HIH, 6 both autosomal dominant and recessive HIH, 2 X-linked HIH, and 3 maternally inherited HIH. Mutations in a single gene may not only cause autosomal dominant, nonsyndromic HIH, but also autosomal recessive, nonsyndromic HIH (GJB2, GJB6, MYO6, MYO7A, TECTA, TMC1), and even syndromic HIH (CDH23, COL11A2, DPP1, DSPP, GJB2, GJB3, GJB6, MYO7A, MYH9, PCDH15, POU3F4, SLC26A4, USH1C, WFS1). Different mutations in the same gene may cause variable phenotypes within a family and between families. Most cases of recessive HIH result from mutations in a single locus, but an increasing number of disorders is recognized, in which mutations in two different genes (GJB2/GJB6, TECTA/KCNQ4), or two different mutations in a single allele (GJB2) are involved. This overview focuses on recent advances in the genetic background of nonsyndromic HIH.

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    • "To date, no fewer than 144 loci have been described and 83 of the associated genes identified for NSHHL (Van Camp and Smith, accessed 12.01.2015). The genes involved code for motor proteins, cytoskeletal, gap-and tight junction components and transcription factors, as well as for factors whose function remains unknown (Finsterer and Fellinger, 2005). Despite this apparent diversity, one gene locus appears to be responsible for more than 50% of all cases of genetic congenital hearing loss: the recessively-inherited DFNB1 (Gasparini et al., 2000;Zelante et al., 1997). "
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    ABSTRACT: Mutations in the GJB2 gene are known to represent the commonest cause of hereditary and congenital hearing loss. In this study, a complete sequencing of the GJB2 gene in a cohort of 506 patients from a single, large cochlear implant program in Europe was performed. Audiological testing for those patients who could actively participate was performed using pure tone audiometry (PTA). Those unable to undergo PTA were measured using click-auditory brainstem response (ABR). Data analysis was performed to determine genotype-phenotype correlations of the mutational status vs. audiological profiles and vs. age at the time of presentation. An overall prevalence of biallelic mutations of 13.4 % was found for the total collective. When subsets of younger patients were examined, the prevalence increased to 27 % of those up to age 18 and 35 % of those up to age 5 at the time of testing, respectively. This increase was found to be highly significant (p < 0.001). Analysis of the mean PTA thresholds revealed a strong correlation between allele combination status and mean PTA (p = 0.021). The prevalence of simple heterozygotes was found to be approximately 10.1 %, which is around 3.3 times the value expected in the general population. As GJB2 follows a recessive pattern of inheritance, the question arises as to why such a large fraction of simple heterozygotes was observed among the hearing impaired patients included in this study.
    No preview · Article · Jan 2016 · Hearing research
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    • "The autosomal recessive loci are called DFNB followed by a number corresponding to the order that the locus was first described; DFNB1 to DFNB96 have been reported so far (see Hereditary Hearing Loss Homepage at more details). It has been estimated that 1% of the human genes, i.e. 200–250 genes, are responsible for hereditary HL [1]. More than 55 genes have been identified to cause HL. "
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    ABSTRACT: Mutations in OTOF have been reported to cause nonsyndromic hearing loss in different populations. The purpose of this study is screening of OTOF mutations in Iranian population. Thirty-eight consanguineous families affected with autosomal recessive nonsyndromic hearing loss (ARNSHL) and negative for GJB2 or GJB6 mutations were screened by autozygosity mapping and Sanger sequencing to find OTOF mutations. A novel homozygous frameshift mutation (c.1981dupG) was found to cause hearing loss in one family and no other OTOF variants were detected in the remaining families. The affected individuals were homozygous forp. D661GfsX2 causing defect in long isoform of otoferlin. We conclude that OTOF mutations are not the major cause of ARNSHL in the Iranian population but still may play an important role in HL; therefore evaluation the OTOF gene is of concern.
    Full-text · Article · Aug 2012 · International journal of pediatric otorhinolaryngology
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    • "The mode of inheritance of prelingual, nonsyndromic hearing impairment is autosomal recessive in 75–80% of cases, autosomal dominant in 10–20%, Xchromosomal recessive in 1–5%, and maternally inherited in 0– 20%. Postlingual nonsyndromic hearing impairment usually follows an autosomal dominant mode of inheritance [4]. A novel, transmembrane inner ear expressed (TMIE/Tmie) gene was found to cause hearing-related disorders when defective in humans and mice [5] [6]. "
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    ABSTRACT: To determine whether variants of the TMIE gene are causes of nonsyndromic deafness in Taiwan. A genetic survey was made from 370 individuals, with 250 nonsyndromic hearing loss and 120 normal hearing individuals. Genomic DNA was extracted from peripheral blood leukocytes and then subjected to PCR to amplify selected exons and flanking introns of the TMIE gene; the amplified products were screened for base variants by autosequence. Data from the two groups were then compared using Fisher's two-tailed exact test and Armitage's trend test. The analysis revealed 7 novel variants in the TMIE gene. Of the 7 variants, 5 variants were found in both nonsyndromic hearing loss and normal hearing group. Both allelic and genotype frequencies of these sequence changes did not differ significantly between patients and controls (P>0.05). However, a missense variant (c.257G>A) and one promoter variant (g.1-219A>T) were found in two patients with nonsyndromic hearing loss. Family study and microsatellite analysis found that c.257G>A variant is not inherited from his parents. The c.257G>A variant encodes a protein with glutamine at position 86 instead of arginine (p.R86Q), a residue that is conserved in mammals but different in fish, and predicted to be extracellular. Despite the fact that the frequency of TMIE variants in our study subjects was low, we suggested that c.257G>A (p.R86Q) variant is a de novo and may be as a risk factor for the development of hearing loss in Taiwanese.
    Full-text · Article · Mar 2010 · International journal of pediatric otorhinolaryngology
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