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研究生:呂盈璋
研究生(外文):Ying-Chang Lu
論文名稱:耳聾的基因診斷:大規模平行定序及基因置換鼠之應用
論文名稱(外文):Genetic Diagnosis of Deafness : Applications of Massively Parallel Sequencing and Knock-in mice
指導教授:翁昭旼翁昭旼引用關係
指導教授(外文):Jau-Min Wong
口試委員:林鴻清劉殿楨
口試委員(外文):Hung-Ching LinTien-Chen Liu
口試日期:2014-01-11
學位類別:博士
校院名稱:國立臺灣大學
系所名稱:醫學工程學研究所
學門:工程學門
學類:綜合工程學類
論文種類:學術論文
論文出版年:2014
畢業學年度:102
語文別:中文
論文頁數:104
中文關鍵詞:遺傳性聽損SLC26A4基因Pendrin基因置換鼠大前庭導水管症候群大規模平行定序
外文關鍵詞:Hereditary hearing lossSLC26A4PendrinKnock-in miceEnlarged vestibular aqueduct syndromeMassively parallel sequencing
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感音神經性聽力損失是各種感覺系統缺陷中最為常見的,在已開發國家如台灣每1000名嬰幼兒當中會有三人患有中至重度聽損,其中三分之二可歸因於遺傳因素,即遺傳性聽損。最近十年來,學界已經發現至少五十多個基因與非症候群遺傳性聽損的發生有關,而特發性感覺神經性聽損的病人中,約有1/3至1/2可以找到常見的耳聾基因變異。由於基因檢測結果,提供了關於病人聽損成因最直接的線索,因此聽損的基因檢測使得今日臨床醫師或聽力師在面對特發性感覺神經性聽損的病人時,都能更正確地基因諮詢和更精確地評估預後。然而,我們目前採用DNA直接定序法或SNaPshot基因檢測法進行聽損的基因檢測,固然能獲得聽損基因突變資料,然而實用上卻仍有其侷限。其一,僅能檢測幾個常見的耳聾基因,而無法針對所有已知的耳聾基因作一全盤性的掃描;其二,於許多家族史明顯的聽損家族,並無法檢測出已知的基因突變,故理論上應有其他未知的耳聾基因導致國人的遺傳性聽損。大規模平行定序(Massively parallel sequencing)技術的發展,應有助於突破此二技術瓶頸。臨床上SLC26A4基因突變的患者經常合併內耳大前庭導水管和急性波動性的聽力喪失,傳統的類固醇療法無法達到滿意的治療效果或正確預估療效。雖然吾人已知基因於聽損之發生扮演極重要的角色,卻無法直接於人體內耳進行研究,乃有賴動物模式的建立。過去幾年的研究證實,同為哺乳類動物的小鼠,為研究遺傳性聽損極佳之動物模式。本研究分為兩大部分,第一部份,應用大規模平行定序於多病例聽損家族之基因診斷,尋找出其他導致國人遺傳性聽損的耳聾基因。第二部分,即在建立實驗動物模式,以釐清基因突變之致病機制。
第一部分,由於經費有限所以先選取12個未能檢測出常見耳聾基因變異,但家族史明顯之多病例家族進行大規模平行定序,針對已知80個耳聾基因,進行基因變異掃描。其後進行資料過濾,包括:基因變異於族群中之對偶基因頻率 <5%、以PolyPhen2及SIFT等電腦軟體進行胺基酸變異之致病性預測值>0.95、直接定序確認、家族樹分析及胺基酸基之演化保留分析等,以釐清所發現之基因變異是否即為導致聽損之真實突變。大規模平行定序的結果於4個顯性遺傳家族確認出4個導致聽損之基因變異,包括:GJB2基因p.R75Q變異、MYO7A基因p.T381M變異、KCNQ4基因p.S680F變異、MYH9基因p.E1256K變異、及GJB4基因p.C169W變異。第二部分,針對國人SLC26A4基因最常見的兩個變異點位c.919-2A.G與p.H723R分別培育出基因置換鼠(Slc26a4tm1Dontuh與Slc26a4tm2Dontuh) 作為研究人類疾病之動物模式。進一步將Slc26a4 c.919-2A>G與p.H723R突變之同型合子基因置換鼠雜交以便得到同時帶有兩個基因突變點之複合異合子之小鼠。聽性腦幹反應檢查記錄其聽力表徵,並進行一系列之平衡功能檢查,內耳細胞形態學檢查,噪音誘發聽損實驗。Slc26a4 基因c.919-2A>G突變之同型合子基因置換鼠Slc26a4tm1Dontuh/tm1Dontuh,表現型可觀察到重度聽損、46%有歪頭及繞圈圈的行為模式,內耳形態學檢查可觀察到前庭導水管和內淋巴囊擴大、內淋巴水腫、血管紋萎縮、耳石變大及變少、毛細胞退化等表徵。然而Slc26a4 p.H723R突變之基因置換鼠Slc26a4tm2Dontuh/tm2Dontuh、以及Slc26a4 c.919-2A>G與p.H723R突變之同型合子基因置換鼠雜交得到同時帶有兩個基因突變點之複合異合子Slc26a4tm1Dontuh/tm2Dontuh之小鼠,表現型可觀察到正常的聽力表現、平衡功能、內耳形態學等表徵。噪音誘發聽損實驗中,表現型和野生型小鼠無異。
應用大規模平行定序技術可作為遺傳性聽損之診斷工具,有助於發現其他導致國人遺傳性聽損的耳聾基因。本研究中所培育出之Slc26a4基因突變的小鼠動物模式與人類波動性聽力喪失之表現型略有不同,所以我們往後希望能建立與人類相同表現之動物模式有助於未來藥物基因體治療策略之研發。


Sensorineural hearing loss is the most common sensory defect, affecting about 3-10 per 1000 children. It is estimated that in developed countries, genetic causes of HL can be found in at least two-thirds of prelingual cases, i.e. hereditary hearing impairment (HHI). To date, more than 50 genes have been related to non-syndromic HHI, and common deafness genetic mutations can be identified in 1/3 to 1/2 of patients with idiopathic SNHI. With little doubt, genetic diagnosis provides direct clues about the pathogenesis of hearing impairment, making it valuable in genetic counseling and predicting the prognosis of the patients. However, conventional genetic testing for deafness using direct sequencing or SNaPshot technique suffers from two limitations. First, a comprehensive screening for all known deafness genes remains infeasible. Second, mutations cannot be detected in some families with obvious family history, implicating the existence of unknown novel deafness genes. The development of Massively parallel sequencing (MPS) might be helpful in overcoming these two technical limitations. Clinically, patients with SLC26A4 mutations are characterized by inner ear malformations and fluctuating hearing loss. For decades, the latter has constituted a treatment difficulty for otologists, because traditional regimens (e.g. steroid) usually could not achieve satisfactory and predictable outcomes. Despite the clinical significance of genetics in HHI, the study of HHI in humans is limited by the inability to perform in vivo experiments. The formidable similarities between the human and mouse inner ears make transgenic mice an excellent model to address HHI in humans. The purpose of Part I of the present study is to searching for novel deafness genes using MPS. The purpose of Part II of the present study is to clarifying their pathogenetic mechanisms using transgenic mouse models.
We applied the MPS technique to 12 multiplex families with idiopathic SNHI in which common deafness mutations had previously been ruled out. NimbleGen sequence capture array was designed to target all protein coding sequences (CDSs) and 100 bp of the flanking sequence of 80 common deafness genes. Initial data filtering with allele frequencies (<5% in the 1000 Genomes Project and 5400 NHLBI exomes) and PolyPhen2/SIFT scores (>0.95) prioritized 5 indels (insertions/deletions) and 36 missense variants in the 12 multiplex families. After further validation by Sanger sequencing, segregation pattern, and evolutionary conservation of amino acid residues, we identified 4 variants in 4 different genes, which might lead to SNHI in 4 families compatible with autosomal dominant inheritance. These included GJB2 p.R75Q, MYO7A p.T381M, KCNQ4 p.S680F, and MYH9 p.E1256K. Among them, KCNQ4 p.S680F and MYH9 p.E1256K was novel. We established knock-in mice model (i.e., Slc26a4tm1Dontuh/tm1Dontuh and Slc26a4tm2Dontuh/tm2Dontuhmice) homozygous for the c.919-2A.G and p.H723R mutation. We further generated mice with compound heterozygous mutations (i.e., Slc26a4tm1Dontuh/tm2Dontuh) by intercrossing Slc26a tm2Dontuh /tm2Dontuh mice with Slc26a4tm1Dontuh/tm1Dontuh mice, which segregated the c.919-2A.G mutation with an abolished Slc26a4 function. Mice were then subjected to audiologic assessments, a battery of vestibular evaluations, inner ear morphological studies, and noise exposure experiments. Slc26a4tm1Dontuh/tm1Dontuh mice revealed profound hearing loss, whereas 46% mice demonstrated pronounced head tilting and circling behaviors. Inner ear morphological examination of Slc26a4tm1Dontuh/tm1Dontuh mice revealed an enlarged endolymphatic duct and sac, atrophy of stria vascularis, deformity of otoconia in the vestibular organs, consistent degeneration of cochlear hair cells, and variable degeneration of vestibular hair cells. Both Slc26a4tm2Dontuh/tm2Dontuh and Slc26a4tm1Dontuh/tm2Dontuh mice showed normal audiovestibular phenotypes and inner ear morphology, and they did not show significantly higher shifts in hearing thresholds after noise exposure than the wild-type mice.
MPS enables genetic diagnosis in multiplex families with idiopathic SNHI by detecting mutations in relatively uncommon deafness genes. In this study, none of these models can perfectly simulate the progressive or fluctuating hearing loss in humans. For the next step, we plan to generate a knock-in mouse model which may better simulate the progressive or fluctuating hearing loss in humans.


CONTENTS

口試委員會審定書   I
致謝 II
中文摘要 III
ABSTRACT V
I. Introduction 1
1.1. Hereditary Hearing Impairment in Humans 1
1.1.1. Clinical significance of hereditary hearing impairment 1
1.1.2. Genetic mutations causing HHI 2
1.1.3. Limitations of HHI studies in humans 5
1.2. Application of the next generation sequencing technique to clinical studies of hereditary hearing impairment 5
1.2.1 Introduction to next generation sequencing 5
1.2.2 Application of NGS to clinical diagnosis of hereditary diseases 6
1.2.3 Application of NGS to searching for novel genes 7
1.3. The Mouse as a Model for Hereditary Hearing Impairment 8
1.3.1. The mouse genome 8
1.3.2. Mouse models for HHI 9
1.3.3. Performing inner ear studies in mouse models 10
1.4. SLC26A4 Mutations and Deafness 11
II. Materials and methods 13
Part I. Massively Parallel Sequencing 13
2.1. Family Recruitment and Phenotype Characterization 13
2.2 Target Enrichment, Massively Parallel Sequencing and Variant Calling 14
2.3 Data Filtering 15
Part II. Knock-in Mice Model 16
2.4. Construction of knock-in mice 16
2.4.1. Slc26a4tm1Dontuh/ tm1Dontuh knock-in mice 16
2.4.2. Slc26a4tm2Dontuh/tm2Dontuh knock-in mice 17
2.5. Phenotype studies 19
2.5.1. Determination of the pathogenesis of the c.919-2A>G and c.2168A>G mutation. 19
2.5.2. Auditory and vestibular evaluations 19
2.5.3. Inner ear morphology studies 20
2.5.4. Expression of pendrin and Kcnj10 22
2.5.5. Noise exposure experiments 22
2.5.6. Thyroid and renal serum biochemistry 23
2.6. Molecular studies 23
2.6.1. Real-time PCR 23
2.6.2. Western blot analysis 24
III. Reslts 25
Part I. Massively Parallel Sequencing 25
3.1. Target Enrichment and Massively Parallel Sequencing 25
3.2. Data Filtering and Identification of Causative Variants 25
3.2.1. Known Causative Variants: GJB2 p.R75Q and MYO7A p.T381M 25
3.2.2. Novel Causative Variants: KCNQ4 p.S680F and MYH9 p.E1256K 26
3.2.3. Probable Non-causative Variant: GJB4 p.C169W 28
Part II. Knock-in Mice Model 28
3.3. Slc26a4 tm1Dontuh mice with the c.919-2A>G mutation 28
3.3.1. Pathogenetic mechanisms of the c.919-2A>G mutation 28
3.3.2. Audiological and vestibular phenotypes 29
3.3.3. Inner ear morphology 30
3.3.4. Thyroid and renal profiles 32
3.4 Slc26a4tm2Dontuh mice with the p.H723R mutation 32
3.4.1. Audiological and vestibular phenotypes 32
3.4.2. Inner ear morphology 33
3.4.3. Immunolocalization and expression of pendrin and Kcnj10 34
3.4.4. Noise exposure experiments 35
IV. Discussion 36
4.1. Application of Massively Parallel Sequencing to Genetic Diagnosis in Multiplex Families with Idiopathic Sensorineural Hearing Impairment 36
4.2. Slc26a4tm1Dontuh mice with the c.919-2A>G mutation 41
4.3. Slc26a4tm2Dontuh mice with the p.H723R mutation 45
V. Future perspectives 51
5.1. Generation of mouse model with other Slc264 mutations, such as p.T416P 51
5.2. Elucidating the role of gastric type proton pump in auditory physiology using the Atp4a knock-out mouse model 52
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