Nuclear and mitochondrial genes mutated in nonsyndromic impaired hearing
ABSTRACT 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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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.International journal of pediatric otorhinolaryngology 08/2012; 76(11):1610-5. DOI:10.1016/j.ijporl.2012.07.030
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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.International journal of pediatric otorhinolaryngology 03/2010; 74(5):489-93. DOI:10.1016/j.ijporl.2010.02.001
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ABSTRACT: To determine whether variants of exons 7, 11, 22 and 28 of the MYO7A gene are causes of nonsyndromic deafness in Taiwanese. We screened a total of 331 unrelated Taiwanese individuals (age range, 4-22 years), including 231 patients with severe to profound nonsyndromic hearing loss and 100 individuals with normal hearing. Genomic DNA was extracted from peripheral blood leukocytes and then subjected to PCR to amplify selected exons and flanking introns of the MYO7A gene; the amplified products were screened for base mutations by autosequence. Data from the two groups were then compared using the chi-square (chi(2)) test. The analysis revealed six variants in 3 out of 4 screened exons and flanking intronic sequences of the MYO7A gene (exons 7, 11, and 22). Three missense variants were found only in patients with hearing loss and were heterozygous, including Arg206Cys, Arg206His and Thr381Met. A variant, c.IVS22+58G>A, was found in intron 22 of the MYO7A gene from both patients and control group. Allele frequencies of c.IVS22+58G>A were shown to be significant between the two groups using chi(2) test (P<0.05). Our results indicate that Arg206 and Thr381 residues in the motor head region of MYO7A protein are critical sites and the mutations of these residues may lead to the development of nonsyndromic deafness.International journal of pediatric otorhinolaryngology 03/2009; 73(6):811-5. DOI:10.1016/j.ijporl.2009.02.009