KISEP Information Korean J Otolaryngol 2003;46:901-14 유전성난청의이해와평가 서울대학교의과대학이비인후과학교실 오승하 Understanding and Assessment of Hereditary Hearing Impairment Seung Ha Oh, MD Department of Otolaryngology-Head & Neck Surgery, Seoul National University College of Medicine, Seoul, Korea - - - 901
유전성난청의이해와평가 - - - - Two-strand Three-strand Four-strand A B C D Bivalents in prophase pf meiosis Gametes Chromatids in gamete Key N Nonrecombinant R Recombinant between R A and B loci Fig. 1. Single and double recombinations occur between markers that are not closely linked. All of the various types of crossover can occur in random proportions. The relationship between RF and genetic distance along the chromosome is calculated using a mapping function. 902 Korean J Otolaryngol 2003;46:901-14
오승하 Table 1. Classification of hearing loss based on audiological phenotype Onset Congenital Early onset childhood Late onset adulthood Type 0.5, 1, 2 khz avg Frequency Severity 0.5, 1, 2, 4 khz avg Progression 0.5, 1, 2 khz avg Laterality Symmetry Linguality Vestibular symptom Tinnitus Varibility intra-familial, inter-familial Sensorineural BC20 db, ABG15 db Conductive BC20 db, ABG15 db Mixed BC20 db, ABG15 db Low 500 Hz Middle 5012000 Hz High 2000 Hz Mild 2140 db Moderate 4160 db Moderately severe 6180 db Severe 81100 db Profound 100 db Progressive 10 db HL within last 10 years Non-progressive Fluctuate Bilateral better ear worse than 20 db HL Unilateral Symmetric Not symmetric 10 db HL difference at least two frequencies Prelingual Postlingual Yes No Yes No Yes No Table 2. Classification of hearing loss based on cause Genetic 5060% Phenotype Syndromic 3040% Non-syndromic 6070% Inheritance Autosomal recessive 7080% Autosomal dominant 1020% X-linked 12% Mitochondrial 1%, variable between ethnic groups Multigenic Chromosomal abnormalities Non-genetic 4050% Teratological CMV, rubella etc. Prematurity Postnatal infection meningitis, otitis media Ototoxic drugs Acoustic or cranial trauma - 903
유전성난청의이해와평가 Table 3. Mendelian syndromes associated with hearing loss Syndrome Gene/locus/ Inheritance Frequency* Clinical features Loci pattern protein Pendred 30 32) AR 4 8% Hearing loss 100%, positive perchloride 1 PDS/ discharge test 95%, radiological 7q22-31.1/ malformations of the cochlea enlarged Pendrin vestibular aqueduct, Mondini dysplasia 85%, goitre 80%, hypothyroidism 40% Usher 11 15)35) AR 3 6% Type 1 USH1AFSevere-profound congenital hearing loss, vestibular dysfunction, retinitis pigmentosa with onset of symptoms in childhood Branchio- oto- Type 2 USH2ACModerate-severe hearing loss, normal vestibular function, later onset retinitis pigmentosa Type 3 USH3Progressive hearing loss, variable onset of retinitis pigmentosa AD 2.0% Hearing loss 90%, preauricular pits 80%, renal 16)17) renal anomalies 65%, branchial fistulae 50%, pinnae deformities 35%, external auditory canal stenosis 30% Waarden Burg 1)10)18 24) AD 1.4% Type IHearing loss bilateral 20%, unilateral 15%, dystopia canthorum 100%, high/broad nasal root 90%, heterochromia irides 35%, white forelock 30%, early greying 20% Type IISame as type I except for absence of dystopia Type III Klein-Waardenburg Camptodactyly and other upper limb defects in addition to Type I findings Type IV Shah-Waardenburg syndrome: Deafness, pigmentary disturbances, and Alport 25)26) AR/XLR 1.0% Haematuria progressing to renal failure, typical electronmicroscopic findings of renal glomerules, eye abnormalities anterior lenticonus, macular flecks, peripheral coalescing flecks, high frequency sensorineural hearing loss Treacher Collins 27) Stapes fixation/ Gusher DFN3 28) Jervell and Lange- Nielsen 4)5) AD 1.0% Symmetrical hypoplastic zygomas with downslanted palpebral fissures, malformed and small external ears with ear tags/pits, bilateral hearing loss frequently conductive 55%, often associated high-frequency sensorineural hearing loss XLR 0.5% Mixed progressive hearing loss starting from early infancy, vestibular abnormalities, perilymphatic gusher following stapedectomy AR 0.25 Hearing loss, prolonged QT interval on electrocardiogram, syncope, seizures, sudden death 10 USH1B MYO7A/ 11q13.5/myosinVIIa Harmonin USH1DCDH23/ 10q21-q22 USH2A/1q41 Function of gene Chloride-iodide transport Unconventional myosin probably involves in USH1C/11p15.1/ organisation of transmembrane proteins, Cadherin-like protein, similar to intercellular adhesion molecules resembles extracellular matrix protein or cell adhesion molecule 2 EYA1/8q13.3 Transcription factor involving development of inner ear and the kidney's metanephric cells. 5 WSI and III PAX3/2q35 WSIIMITF/ 3q14.1-p12.3 WSIVEDNRB/ 13q22/endothelin receptor B homozygous mutations EDN3/20q13.2- q13.3/endothelin-3 aganglionic megacolon homozygous mutations) SOX10/ 22q13/ heterozygous mutations 3 COL4A5/Xq22/ Collagen IV alpha-5 80% COL4A3 and COL4A4/2q36q37/ collagen IV alpha 3 and 4 AR 1 TCOF1 Treacle/ 5q32-q33.1 PAX3, SOX 10 and MITF are transcription factors that are part of a cascade of proteins working on the proteins responsible for skin, eye, inner ear, face, limbs and neural crest development Endothelin 3 and endothelin are receptor B in endothelin-signalling pathways Formation of basement membrane in the cochlea, eye and kidney. Nuclear-cytoplasmic transport 1 POU3F4/Xq21 Transcription factor 2 KVLQT1/11p15.5 KCNE1/21q22.1- q22.2 Formation of a delayed rectifier potassium in the inner ear In severe to profound early-onset deaf population, See further reading section, AD=autosomal dominant, AR=autosomal recessive, XLR=X-linked recessive. Adopted from Tekin M, Arnos KS, Pandya AAdvances in hereditary deafness. Lancet 2001358(9)1082-1090 904 Korean J Otolaryngol 2003;46:901-14
오승하 Table 4. Summary of cloned non-syndromic sensorineural hearing loss genes DFNA Chromosomal locus Gene Gene function Comments on phenotype 01 5q31 HDIA1 Diaphanous Cytokinesis and cell polarity 02 1p34 GJB3 Connexin 31 Gap junction, potassium recycling Sensorineural neuropathy with deafnesserythrokeratodermia variabilis without deafness KCNQ4 Potassium channel, potassium recycling 03 13q12 GJB2 Connexin 26 Gap junction, potassium recycling Palmoplantar keratoderma GJB6 Connexin 30 in some families 05 7p15 DFNA5 ICERE-1 Unknown 08 11q22-q24 TECTA tectorin Structural protein in the tectorial membrane 09 14q12-q13 COCH Extracellular protein; maintenance of Menière's disease cochlear cells 10 6q22-q23 EYA4 Transcription factor 11 11q12-q21 MYO7A Myosin 7A Unconventional myosin; structural and Usher syndrome type IB functional component of stereocilia 12 11q22-q24 TECTA tectorin Same as DFNA8 13 6p21 COL11A2 Structural protein in cochlea Stickler syndromemarshall syndrome 15 5q31 POU4F3 Transcription factor DFNB 01 13q12 GJB2 Connexin 26 Same as dominant 02 11q13.5 MYO7A Myosin 7A Same as dominant Usher syndrome type IB 03 17p11.2 MYO15 Myosin 15 Unconventional myosin 04 7q31 PDS Pendrin Anion transporter Pendred syndrome 08 21q22 TMPRSS3 Transmembrane protein 09 2p22-p23 OTOF Otoferlin Vesicle-membrane fusion 10 21q22 TMPRSS3 Transmembrane protein 12 10q21-q22 CDH23 Transmembrane and extracellular domains Usher syndrome 1D possibly cell-cell adhesion 21 11q TECTA tectorin See DFNA8 29 21q22 DFNB9 Claudin-14 Tight junction protein DFN 01 Xq22 DDP Neurological development 03 Xq21 POU3F4 Transcription factor Perilymphatic gusher Adapted from the hereditary hearing loss homepage www.uia.ac.be/dnalab/hhhand Tekin M, Arnos KS, Pandya AAdvances in hereditary deafness. Lancet 200135891082-1090 905
유전성 난청의 이해와 평가 이르는 어느 단계에서든 이상이 발생하면 나타날 수 있다. Enlarged Vestibular Aqueduct Mondini 기형과 동반 대부분의 유전성 난청은 내이의 이상에 의한 감각신경성 하여 자주 발견된다. 유아기부터 시작되어 점차 나이가 들 난청이지만 드물지 않게 중이 이소골의 기형이나 진행성 면서 진행성 난청을 보인다. Pendred s syndrome에서 고정(fixation) 혹은 외이도의 기형에 의한 전음성 난청도 나타난다. 일으킬 수 있다. 태생기 9주까지 와우는 완전히 발달되어 Semicircular Canal Malformations 세반고리관은 태 2와 3/4회전을 한다. 태아에서 내이의 발생과정에 문제가 생기 6주 경부터 발달된다. Superior canal이 가장 먼저 발생하면 특정세포의 형성부전으로부터 내이의 기형까지 생기고 lateral canal이 맨 마지막에 완성된다. 그러므로 다양한 원인에 의한 선천성 난청을 초래한다. 전산화단층 lateral canal의 이상이 가장 많이 발견되고 superior의 이 촬영을 이용하면 선천성 감각신경성난청 환자의 약 20% 상은 lateral 이상을 동반하여 발견된다. 에서 내이의 기형을 발견할 수 있다. 다음은 특징적으로 Fig. 2에서는 Michel aplasia부터 Mondini aplasia사이 의 기형 중 내이의 발생이 정지된 시기별로 보다 자세히 발견되는 내이의 기형이다. Michel Aplasia 태생기 3주 이내에 문제가 발생하여 분류한 것을 소개하였다. 완전히 내이가 없는 기형이다. 아직 원인 유전자는 밝혀져 있지 않다. 청각기능과 관련된 유전자들(Fig. 3) Mondini Aplasia 태생기 6~7주 경 문제가 발생한 경 정상적인 내이기능을 유지하는 여러 단백물질의 이상은 우로 와우의 기저부만 발달되고 첨부는 불완전 발달을 보 내이의 구조에 기형을 초래하지는 않지만 내이의 항상성 인다. Pendred, Waardenburg, Treacher Collins, Wilder- (homeostasis)장애를 일으켜 난청이 초래된다. 코티기관에 vaank syndrome에서 보이고 CMV 감염과 같은 비유전 는 내유모세포(inner hair cell)와 외유모세포(outer hair 성 난청에서도 보인다. cell)가 있다. 내유모세포는 음의 진동에 의한 운동에너지 Scheibe Aplasia(Cochleosaccular dysplasia or pars 를 신경의 활동전위로 바꾸어주는 역할을 한다. 음의 진동으 inferior dysplasia) 와우 내 코티기관과 tectorial mem- 로 기저막(basilar membrane)이 움직임에 따라 유모세포 brane의 이상을 보이고 골성미로(bony labyrinth)와 평형 첨부의 stereocilia가 tectorial membrane과 반대 방향으로 감각기관에는 이상이 없는 경우이다. 내이기형 중 가장 많 움직이며 굴곡하게 된다. Stereocilia는 그 옆의 stereocilia 이 발생하며 비증후군성 상염색체 열성유전을 보인다. 측 와 tip link라는 filament로 연결되어 있으며 kinocilium 두골 단층촬영에서는 정상으로 보인다. 방향으로 굴곡할 때 수동적으로 포타슘(K+) cannel이 열 Alexander Aplasia 기저부의 와우에 국한하여 막성미 려 내림프에 풍부한 포타슘 이온이 유모세포 안으로 들어 로의 기형이 발생하며 청력검사 상 고음역의 난청을 보인 가게 된다. 포타슘 이온은 유모세포에서 활동전위를 발생 다. 측두골 촬영은 정상소견이다. 시키고22) 세포의 기저부(basolateral side)를 통하여 기저 ① ④ 906 ② ⑤ ③ ⑥ Fig. 2. Classification of cochleaovestibular anomaly (adpted from levent sennaroglu, Laryngoscope, 112 2230-41, 2002). ① Michel deformity (3rd week). ② Cochlear aplasia (late 3rd week). ③ Common cavity (4th week). ④ IP-I Cystic cochleaovestibular malformation (5th week). ⑤ Cochleaovestibular hypoplasia (6th week). ⑥ IP-II Classical mondini deformity (7th week). Korean J Otolaryngol 2003;46:901-14
오승하 KVLQT1 and KCNE1 Mesenchymal cells Stria vascularis Marginal cells PDS TECTA and COL11A2 [K + ] Spiral prominence epithelium Tectorial membrane [K + ] ATP6B1 Interdental cells GJB2 and GJB3 MYO7A, POU4F3, and KCNQ4 Outer hair cells Supporting cells Inner hair cell GJB2 OTOF and KCNQ4 Fig. 3. Cross-sectional view of the inner ear through the base of the cochlea. Adapted from Tekin M, Arnos KS, Pandya AAdvances in hereditary deafness. Lancet 2001 35891082-1090. - - - 내림프의이온분비와순환에관련된유전자 907
유전성난청의이해와평가 - - 908 세포골격단백유전자 - 기타코티기관내구성단백유전자 Korean J Otolaryngol 2003;46:901-14
오승하 미토콘드리아유전자 - db 0 10 125 250 500 1k 2k 4k 8k (Hz) db 0 10 125 250 500 1k 2k 4k 8k (Hz) 30 50 1 30 50 70 70 2 4 3 90 90 110 Femal e mutant with normal hearing 110 1. F/74 SNHL (onset;2ya) 5 6 Mal mutant with hearing loss e 6. F/8 Pedigree of the family with the mutation 125 250 500 1k 2k 4k 8k (Hz) 125 250 500 1k 2k 4k 8k (Hz) 125 250 500 1k 2k 4k 8k (Hz) 125 250 500 1k 2k 4k 8k (Hz) db db db db 0 0 0 0 10 10 10 10 30 30 30 30 50 50 50 50 70 70 70 70 90 90 90 90 110 110 110 110 2. F/41 SNHL (onset;7ya) 3. M/35 SNHL (onset;6ya) 4. F/38 5. M/12 Fig. 4. Pedigree and audiograms for six family members with 1555 mutation. Below the pedigree are the number of each familial members who showed mutation. Three members case 1, 2, and 3 show moderate to severe sensorineural hearing loss while the others case 4, 5, and 6 show nearly normal hearing. The patient number 2 denied any usage of aminoglycoside. Note that the children show completely normal hearing even though they have a mutant gene. 909
유전성난청의이해와평가 Fig. 5. A:Common pedigree symbols, definitions and abbreviations. B:Pedigree line definitions Adapted from Bennett et al., 1995 910 Korean J Otolaryngol 2003;46:901-14
오승하 - - - 911
유전성 난청의 이해와 평가 초기 메뉴 유전정보 입력 청력검사 입력 가계도 입력 Fig. 6. IZMIR 프로그램 (독일 Tuebingen 대학). ③ 우리나라에서 흔한 유전성 난청을 저렴하고 정확하 등의 증후군성 난청 원인 유전자가 밝혀져 왔다. 비증후군 성 난청의 경우에도 최근 몇 년간의 연구로 40개가 넘는 게 진단하는 방법을 개발. ④ 난청을 조기에 발견하기 위한 선별검사를 전국적으로 유전성 난청의 원인이 밝혀졌으며 앞으로 300개 이상의 유전자가 더 밝혀질 것으로 예상된다. 향후 난청과 관련된 시행하고 표준화 하는데 기여 유전자의 수는 더욱 빠른 속도로 밝혀질 것이며 궁극적으 Fig. 6은 독일은 튜빙겐 대학에서 개발한 난청환자 기록 로 유전성난청의 연구를 통하여 난청의 원인이 되는 유전 프로그램이다. 이 프로그램을 이용하여 유럽의 여러 대학 적 결함이 밝혀지고 난청의 기전을 이해할 수 있게 될 것 과 연구기관에서 공동으로 환자 정보를 입력하고 난청 유 이다. 결과 그 동안 베일에 싸여 있던 내이청각기관의 발 전자 검사를 위한 검체를 수집한다. 우리나라에서도 전국 생에 관련된 조절인자나 내이의 항상성 유지에 필요한 유 적인 네트워크를 구축하는데 표준 방법으로 이러한 프로그 전자들의 기능 등이 더욱 자세히 알려질 것이다. 또한 이 램을 이용하여야 할 것이다. 를 이용한 진단방법, 조기진단에 따른 예방 및 치료방법 연구, 유전자 치료의 가능성 등에 대한 연구가 가속화될 결 론 것이다. 유전성 질환은 인종에 따른 차이가 분명히 존재한다. 앞으 최근 분자유전학의 기술이 발달되면서 가장 흔하게 접하 로 한국의 유전성 난청질환 환자에게서 어느 유전자의 결함 게 되는 감각신경성 난청, 특히 비증후군성 선천성 난청의 이 관련되었는지 검사를 수행하고 효과적으로 screening 원인 유전자들이 하나씩 밝혀지고 있다. 지금까지 Usher 할 수 있는 방법을 찾아내며 한국인에 특이한 유전자 이상 syndrome, Waardenburg syndrome. Alport syndrome, 을 밝혀내어야 한다. 이를 위하여 여러기관이 공동으로 연 Norrie syndrome, BOR syndrome, Pendred syndrome 구하는 네트워크를 구축하고 난청 유전자 정보 등록 체계 912 Korean J Otolaryngol 2003;46:901-14
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