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Clinical Evaluations and Mutational Analysis for Late-onset Progressive Hearing Loss

Author: Sun
Tutor: HanDongYi;YuanHuiJun
School: PLA Postgraduate Medical School
Course: Department of Otolaryngology
Keywords: hearing loss DFNA gene mutation analysis late-onset autoimmune sensorineural hearing loss COCH GJB3
CLC: R764.43
Type: PhD thesis
Year: 2007
Downloads: 167
Quote: 1
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Hearing impairment is the most common perception disorder in the world. Approximately 1 in 1000 children is born with pre-lingual deafness, and it is estimated that in developed countries, 60% of these cases are genetic in origin. Post-lingual hearing loss is even more common and it affects 10% of the population by the age of 60 and 50% by the age of 80. Age related late-onset hearing loss is also a heterogeneous trait with many suspected causes. Genetic factors, including mitochondrial mutations, and environmental factors, such as noise exposure, may contribute to the trait. The second national survey on disability in 2006 indicated that the number of population with hearing impairment had reached 20.04 million in china.In this study, we have recruited 34 Chinese DFNA families, 29 small families which the inheritance pattern could not be recognized, 37 sporadic patients with late onset sensorineural nonsyndromic hearing loss, and 22 patients with autoimmune sensorineural hearing loss through the Institute of Otolaryngology, Chinese PLA General Hospital.Part one: The mutational and functional study related to COCH and non-syndromic autosomal dominant sensorineural hearing loss (DFNA9) has recently attracted much attention in the research area of genetics on hearing loss. To date, nine distinct mutations (V66G, G88E, W117R, P51S, I109N, A119T, V104del, G87W, and C542F) have been reported in 15 DFNA9 families worldwide. But there is no such report in the Chinese population. In previous study, we genetically mapped the gene defect underlying a progressive non-syndromic autosomal dominant sensorineural hearing loss in a large Chinese family SD-Z01 to a 7.6 cM region on 14q12-q13, overlapping with the DFNA9locus. In this study, mutation analysis of the COCH revealed a missense mutation C542Y at an evolutionarily conserved cysteine residue in the vWFA2 domain of cochlin. Furthermore, we screened the mutation of COCH in 33 additional DFNA families as well as in 29 small families (the inheritance pattern could not be recognized) and 37 sporadic patients with Chinese background with late onset progressive sensorineural hearing loss. A heterozygous 1535 T>C mutation leading to M512T substitutions was identified in the vWFA2 domain in a small family 267. Both the residues of Cys542 and M512 are conserved across human, mouse, chicken, and zebrafish. It is likely that the cochlin cysteine residues flanking the second vWFA domain at positions 362 and 542 form an intrachain disulfide bond. Disruption of this putative intrachain C362-C542 disulfide bond in the mutant cochlin allele would interfere with the normal function of this domain or may lead to formation of intermolecular disulfide bonds between cochlin and/or other extracellular matrix protein. The exact functional implication of the M512T mutation remains to be elucidated since the 3D structure of vWFA domain is not available. The C542Y and the M512T mutations cause hearing loss in these two families.Part two: Comprehensive audiological and vestibular evaluations were conducted to identify the clinical features of hearing and vestibular impairment in SD-Z01 and 267 Chinese families, including pure tone audiometry, auditory brainstem response (ABR ) 、 electrocochleogram (EcochG) 、 oculomotor testing, caloric tests (44°C, 30°C), rotational testing, computerized dynamic posturography and vestibular evoked myogenic potentials (VEMP). Based on the questionnaires data, members of the family SD-Z01 showed variable age of onset of hearing impairment that varied from the 2nd to the 5th decade of life. The hearing loss first affected the high frequencies and later involved all frequencies. Overall the audiograms of affected members have a downward sloping contour. Audiologic evaluation of the other family members demonstrates normal immittance testing and bone conduction values that equal the air conduction measurements, suggesting sensorineural hearing impairment. Tinnitus at the onset of hearing loss was reported in 82% affected members. In family 267, the proband began suffering bilateral hearing loss at the age of 43. At the onset of hearing loss,she suffered tinnitus in left ear. Audiological evaluation showed that she had moderate to severe hearing loss with a mountain-shaped pattern. The vestibular symptoms consisted of instability in darkness, a tendency to fall sideways, light-headiness, a drunken feeling, and attacks of vertigo, were not reported by any affected subjects of family SD-Z01 and 267.The extensive vestibular evaluation indicated that all of six affected members of SD-Z01 family performed normally in computerized dynamic posturography and caloric testing. Impairment of the saccular otolith in all of six affected members was suggested by results of the VEMP test. The velocity step test generated abnormal time constants and sinusoidal oscillation test generated abnormal gains and phase in affected members indicated that horizontal canal vestibular hyporeflexia in history. All six affected subjects examined in this family showed completely normal ocular motor responses in oculomotor testing, including smooth pursuit, optokinetic nystagmus, gaze and saccade. The extensive vestibular evaluation for the proband of 267 family was completely normal. The predominant feature of the Chinese DFNA families were that all the affected subjects harboring COCH mutations in the vWFA2 domain didn’t suffer the vestibular symptoms during their life time and comprehensive vestibular assessment revealed only subtle vestibular hypofunction in affected members of SD-Z01 family. Our finding provides the evidence of a genotype-phenotype correlation in DFNA9.Part three: The connexins are a family with at least 20 homologous proteins in humans that form aqueous channels connecting the interiors of coupled cells and mediating electrical and chemical communication. Mutations in the GJB3 gene which encodes connexin31 (Cx31) can cause a dominant non-syndromic form of hearing loss (DFNA2). We screened 31 Chinese DFNA families (in each family affected members ≥5). Mutation analysis revealed that 6 cases carried 2 kinds of GJB3 sequence variants which were known polymorphisms. These findings suggest that mutations in GJB3 may be not common in Chinese DFNA populations.Part four: In 1979, McCabe first brought attention to autoimmune sensorineural hearing loss (ASNHL) which typically produces a bilateral rapidlyprogressive loss of hearing that may occur suddenly. The diagnosis is made by excluding ototoxicity, systemic disease, and other factors that mimic ASNHL and by showing a therapeutic response to corticosteroid treatment. Understanding of ASNHL has been hindered by the inaccessibility of the inner ear to biopsy and the lack of workable animal models. Baek MJ’s study show T cell responsiveness to an inner ear-specific protein in ASNHL patients, and implicates cochlin as a prominent target Ag for mediating autoimmune inner ear inflammation and hearing loss. To investigation the potential relationship between the ASNHL and COCH mutation, a mutation screening of COCH was constructed among 22 cases with ASNHL. None of polymophsims and mutations is found in these cases.In conclusion, this study characterized the profile of COCH and GJB3 genetic variations in Chinese late-onset hearing loss cases. The C542Y and the M512T COCH mutations cause hearing loss in two DFNA9 families. These data provide basic information of genetic approaches to the early diagnosis and prediction of recurrent risks for hearing loss in Chinese population. Developing the relationship between the ASNHL and COCH mutation that may define the stages leading to the development of ASNHL and may also provide new diagnostic markers and help develop novel and effective treatments for preventing progressive hearing loss in ASNHL.

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CLC: > Medicine, health > Otorhinolaryngology > Otology,ear disease > Ear nervous system diseases > Deaf
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