【摘要】：研究背景和目的 伴有皮質(zhì)下梗死和白質(zhì)腦病的常染色體顯性遺傳性腦動(dòng)脈病(cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, CADASIL)是一種非動(dòng)脈硬化、非淀粉樣變的遺傳性動(dòng)脈疾病,是一種成年發(fā)病的單基因遺傳性卒中疾病。因CADASIL患者的臨床表現(xiàn)和影像學(xué)特征復(fù)雜多變,確診仍有賴于皮膚活檢或基因檢測。目前皮膚小動(dòng)脈平滑肌細(xì)胞外噬鋨顆粒的沉積,被認(rèn)為是CADASIL的特征性病理學(xué)改變,然而,電子顯微鏡(electron microscope,EM)評估皮膚小動(dòng)脈的噬鋨顆粒不夠敏感,假陰性率可高達(dá)50%；不同的研究也表明該檢查的敏感性是千差萬別的。故目前NOTCH3基因突變檢測仍然是診斷CADASIL的金標(biāo)準(zhǔn)。 現(xiàn)全世界已報(bào)道該病的500多個(gè)家系,已發(fā)現(xiàn)190多種不同NOTCH3基因突變,包括錯(cuò)義點(diǎn)突變,剪切突變和缺失突變,其中95%為點(diǎn)突變,幾乎90%的突變位于2-6號外顯子,尤以4號、3號外顯子多見。為此,對于臨床疑似患者,行上述局限性外顯子檢查,可以對疾病作出快速診斷。但是,最近研究發(fā)現(xiàn),不同地域CADASIL患者的基因突變好發(fā)位點(diǎn)和基因檢出率存在不同,這可能是種族差異所致,也可能存在其它因素,因即使在同一種族人群,位于不同地域的患者的基因突變好發(fā)位點(diǎn)也存在不同。故在制定基因檢查策略時(shí)需要考慮患者的種族、地域差異性,通過基因檢測進(jìn)一步完善疾病的診斷。迄今為止,國內(nèi)報(bào)道的外顯子突變無明顯聚集性,已發(fā)現(xiàn)的突變位于2號、3號、4號、6號、10號、11號、18號和20號外顯子,也尚無較大樣本OTCCH3基因突變檢出率的研究。 另外由于OTCH3基因存在33個(gè)外顯子,目前檢測到的突變位點(diǎn)廣泛分布在2-23號外顯子內(nèi),基因突變檢測價(jià)格昂貴,耗費(fèi)時(shí)間長,不能作為診斷疾病的常規(guī)方法。如何能夠根據(jù)臨床特征,影像學(xué)特征分析,發(fā)現(xiàn)有效的特征用于篩選合適的基因檢測患者,也是目前臨床研究的熱點(diǎn)之一。 本課題對一組臨床疑診為CADASIL的患者進(jìn)行NOTCH3基因2-23號外顯子突變研究,在此基礎(chǔ)上對其臨床特征和影像學(xué)特征進(jìn)行比較分析,旨在(1)了解該組患者的NOTCH3基因突變情況,明確診斷并了解我國國內(nèi)CADASIL患者基因突變的熱點(diǎn)分布情況和基因突變檢出率情況,為制定合適的基因診斷流程提供依據(jù)；(2)根據(jù)基因檢測結(jié)果,對突變組和無突變組的臨床特點(diǎn),影像學(xué)特征進(jìn)行比較分析,并對突變組內(nèi)患者的臨床特點(diǎn)和影像學(xué)特征進(jìn)行分析,以期發(fā)現(xiàn)可用于判斷適合基因篩查的有效特征。 研究包括以下兩個(gè)部分： 第一部分WTCH3基因突變的研究 目的 明確該組患者的NOTCH3基因突變情況,明確診斷并了解我國國內(nèi)CADASIL患者基因突變的熱點(diǎn)分布情況和基因突變檢出率情況,為制定合適的基因診斷流程提供依據(jù)。 方法 對來自我國華東地區(qū)的35個(gè)無關(guān)家庭的35例臨床疑診為CADASIL的患者行NOTCH3基因2-23號外顯子基因突變分析；同時(shí)對先證者存在NOTCH3基因突變的8個(gè)家系的17例家系內(nèi)成員進(jìn)行相應(yīng)突變外顯子檢測；通過設(shè)立家系外100例正常健康對照來驗(yàn)證所有檢測到致病突變；根據(jù)檢測結(jié)果,計(jì)算NOTCH3基因突變檢出率,并結(jié)合文獻(xiàn)分析我國國內(nèi)OTCH3基因的突變熱點(diǎn)分布區(qū)。結(jié)果 我們在13個(gè)家系中檢測到了9種不同的錯(cuò)義點(diǎn)突變(p.C43Y,p.R90C, p.R110C, p.R133C, p.R141C, p.C144S, p.R153C, p.C155W, p.R182C),其中p.C43Y突變和p.C155W突變在國際上首次被發(fā)現(xiàn)；該組患者中NOTCH3基因的突變檢出率為37.1%(13/35),所有檢測到的致病突變均位于2號、3號和4號外顯子中。另外在1個(gè)家系的22號外顯子中檢測到一目前意義不明的多態(tài)改變(p.R1175W),在3號和4號外顯子分別檢測到一個(gè)不涉及氨基酸改變的多態(tài)c.C303T和c.A606G. 結(jié)論 1)p.C43Y突變和p.C155W突變是兩種新的錯(cuò)義點(diǎn)突變,目前國內(nèi)外尚未報(bào)道。 2) NOTCH3基因4號外顯子和3號外顯子是我國大陸華東地區(qū)CADASIL患者的突變熱點(diǎn)分布區(qū)。 3)該組臨床疑診CADASIL患者的NOTCH3基因突變檢出率僅為37.1%,提示可能存在其他致病基因。 4) NOTCH3基因22號外顯子p.R1175W改變可能與CADAS幾發(fā)病有關(guān)。 第二部分CADASIL的臨床和影像學(xué)特征研究 目的 在基因檢測基礎(chǔ)上,對NOTCH3基因突變組和無突變組的臨床特點(diǎn),影像學(xué)特征進(jìn)行分析,以期發(fā)現(xiàn)可用于判斷適合基因篩查的有效特征。 方法 對能獲得詳細(xì)的臨床資料并完成頭顱磁共振掃描的25例NOTCH3基因突變患者和22例NOTCH3基因無突變患者的臨床特點(diǎn)和影像學(xué)特征進(jìn)行比較分析,并對突變組患者的臨床特點(diǎn),影像學(xué)特征以及認(rèn)知功能與影像學(xué)特征之間的關(guān)系進(jìn)行分析。應(yīng)用SPSS14.0統(tǒng)計(jì)學(xué)軟件進(jìn)行分析,計(jì)量資料以±s表示,并行獨(dú)立樣本t檢驗(yàn)或Mann-Whitney U分析,計(jì)數(shù)資料行Fisher精確檢驗(yàn),統(tǒng)計(jì)學(xué)顯著性水平定為雙側(cè)檢驗(yàn),P0.05為差異有統(tǒng)計(jì)學(xué)意義。 結(jié)果 1.臨床特點(diǎn)方面：兩組在發(fā)病年齡(38.36±7.98vs49.05±8.41,p0.001),入組年齡(45.52±9.61vs51.91±8.71,P=0.022),陽性家族史(78.6%vs33.3%,p=0.015),高血壓病患病率(8.0%vs40.9%,p=0.014)和既往降壓藥物使用(8.0%vs40.9%,p=0.014)的差異有統(tǒng)計(jì)學(xué)意義,而其他腦血管病危險(xiǎn)因素,以及既往降壓,抗栓藥物使用方面的差異無統(tǒng)計(jì)學(xué)意義； 2.影像學(xué)方面：基因突變組腦白質(zhì)高信號體積(70.81±44.90vs42.24±22.24,p=0.025)與無突變組相比差異有統(tǒng)計(jì)學(xué)意義,且累及顳極(72.0%vs27.3%,p=0.003),外囊(84.0%vs27.3%,p0.001)明顯較基因無突變組高,兩組之間有統(tǒng)計(jì)學(xué)差異,但兩組在腦干白質(zhì)高信號,腦內(nèi)腔隙灶的檢出率,分布部位(皮質(zhì)下,皮層,腦干)兩組之間的差異無統(tǒng)計(jì)學(xué)意義,而在腦內(nèi)腔隙灶數(shù)目上(5.33±3.96vs2.00±2.45,p=0.007),突變組明顯較無突變組增多,差異有統(tǒng)計(jì)學(xué)意義。腦內(nèi)微出血灶發(fā)生率,腦內(nèi)微出血灶數(shù)目和MRA上顱內(nèi)大動(dòng)脈狹窄均無統(tǒng)計(jì)學(xué)差異。突變組患者的MMSE評分與腦白質(zhì)高信號體積、腦內(nèi)腔梗灶數(shù)目呈負(fù)相關(guān),而與腦內(nèi)微出血程度無明顯相關(guān)。3.對存在MRA顱內(nèi)大動(dòng)脈狹窄的NOTCH3基因突變患者進(jìn)一步分析發(fā)現(xiàn),有顱內(nèi)大動(dòng)脈病變的CADASIL患者高膽固醇血癥的患病率(62.5%vs17.6%,p＝0.061)和高血壓患病率(40.0%vs0.0%,p＝0.065)較無顱內(nèi)大動(dòng)脈病變的CADASIL有增高的趨勢,但因受病例數(shù)少的影響,沒有明顯的統(tǒng)計(jì)學(xué)差異。兩者在臨床特征、腦血管病危險(xiǎn)因素及影像學(xué)特征方面的差異均無統(tǒng)計(jì)學(xué)差異。結(jié)論 1、影像學(xué)上出現(xiàn)嚴(yán)重腦白質(zhì)病變累及顳極和基底節(jié)外囊區(qū),陽性家族史可以作為臨床診斷CADASIL的有利指標(biāo),發(fā)病年齡小于45歲有利于CADASIL診斷,而臨床表現(xiàn)(頭痛,卒中,精神障礙和認(rèn)知功能障礙)和影像學(xué)上出現(xiàn)皮質(zhì)下腔梗灶、皮層梗死灶和腦內(nèi)微出血不能用于區(qū)分NOTCH3基因突變患者與無突變患者。 2、存在腦血管病危險(xiǎn)因素和顱內(nèi)大動(dòng)脈狹窄不能作為CADAS幾的排除標(biāo)準(zhǔn)。 3、CADASIL患者認(rèn)知功能可能與腦白質(zhì)高信號體積、腦內(nèi)腔隙灶數(shù)目呈負(fù)相關(guān),但與腦內(nèi)微出血的嚴(yán)重程度無明顯相關(guān)。
[Abstract]:Research background and purpose
Autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a non-atherosclerotic, non-amyloid, inherited arterial disease, and a monogenic, inherited stroke disease in adults. The clinical manifestations and imaging features of CADASIL are complex and changeable, and the diagnosis still depends on skin biopsy or gene detection. At present, the deposition of osmium-phagocytic granules in the smooth muscle cells of cutaneous arterioles is considered to be a characteristic pathological change of CADASIL. However, electron microscopy (EM) is used to evaluate osmium-phagocytic granules in cutaneous arterioles. Insufficient sensitivity, false negative rate can be as high as 50%; different studies also show that the sensitivity of the test is very different. Therefore, NOTCH3 gene mutation detection is still the gold standard for the diagnosis of CADASIL.
More than 190 NOTCH3 gene mutations, including missense point mutation, shear mutation and deletion mutation, have been found in more than 500 families worldwide. Of these mutations, 95% are point mutations, and almost 90% are located in exons 2-6, especially exons 4 and 3. For this reason, the above-mentioned limited exons were examined in clinically suspected patients. Rapid diagnosis can be made. However, recent studies have found that CADASIL patients in different regions have different gene mutation prone sites and gene detection rates, which may be due to racial differences, but there may also be other factors, because even in the same ethnic group, patients in different regions of the gene mutation prone sites are not there. So far, there is no obvious aggregation of exon mutations reported in China, and the mutations are located in exons 2, 3, 4, 6, 10, 11, 18 and 20, and there is no large sample OTCCH3. Detection rate of gene mutation.
Because there are 33 exons in OTCH3 gene, the mutation sites detected are widely distributed in exon 2-23. The detection of gene mutation is expensive and time-consuming, so it can not be used as a routine method to diagnose diseases. Detection of patients is also one of the hot topics in clinical research.
The purpose of this study was to investigate the mutation of NOTCH3 gene exon 2-23 in a group of patients suspected of CADASIL, and to compare the clinical and imaging features of NOTCH3 gene mutation in order to (1) understand the mutation of NOTCCH3 gene in this group, diagnose and understand the hot spot distribution of gene mutation in CADASIL patients in China. (2) According to the results of gene detection, the clinical characteristics and imaging characteristics of mutation group and non-mutation group were compared and analyzed, and the clinical characteristics and imaging characteristics of patients in mutation group were analyzed, so as to find out the suitable gene for gene diagnosis. The effective characteristics of screening.
The research includes the following two parts:
Part one research on the mutation of WTCH3 gene
objective
To determine the mutation of NOTCH3 gene in this group, to diagnose and understand the hotspot distribution of gene mutation and the detection rate of gene mutation in CADASIL patients in China, and to provide the basis for the establishment of appropriate genetic diagnosis process.
Method
The exon 2-23 mutation of NOTCH3 gene was analyzed in 35 suspected CADASIL patients from 35 unrelated families in eastern China, and the corresponding mutation exons were detected in 17 members of 8 families with NOTCH3 gene mutation in the proband, and 100 normal controls were set up outside the family. To verify all detected pathogenic mutations, NOTCH3 gene mutation detection rate was calculated according to the results of detection, and the mutation hotspot distribution of OTCH3 gene in China was analyzed combined with the literature.
Nine different missense point mutations (p.C43Y, p.R90C, p.R110C, p.R133C, p.R141C, p.C144S, p.R153C, p.C155W, p.R182C) were detected in 13 families, of which p.C43Y mutation and p.C155W mutation were first found in the world; the mutation rate of NOTCH3 gene in this group was 37.1% (13/35) and all the detected pathogenic mutations were found. In addition, an unidentified polymorphism (p.R1175W) was detected in exon 22 of one family, and a polymorphism c.C303T and c.A606G were detected in exons 3 and 4, respectively.
conclusion
1) p.C43Y mutation and p.C155W mutation are two new missense point mutations, which have not been reported at home and abroad.
2) Exon 4 and exon 3 of NOTCH3 gene are mutation hotspots of CADASIL patients in eastern China.
3) The detection rate of NOTCH3 gene mutation in suspected CADASIL patients was only 37.1%, suggesting the existence of other pathogenic genes.
4) the change of p.R1175W in exon 22 of NOTCH3 gene may be related to the pathogenesis of CADAS.
The second part is the clinical and imaging features of CADASIL.
objective
On the basis of gene detection, the clinical features and imaging features of NOTCH3 gene mutation group and non-mutation group were analyzed in order to find out the effective features for gene screening.
Method
The clinical and imaging characteristics of 25 patients with NOTCH3 gene mutation and 22 patients without NOTCH3 gene mutation were compared and analyzed. The clinical and imaging characteristics of the patients with NOTCH3 gene mutation and the relationship between cognitive function and imaging characteristics were analyzed. SPSS14.0 statistical software was used to analyze the data. The measurement data were expressed as (+) s, and the independent sample t test or Mann-Whitney U analysis were performed. The counting data were analyzed by Fisher exact test. The statistical significance level was determined as bilateral test, and the difference was statistically significant (P 0.05).
Result
1. Clinical characteristics: The age of onset (38.36+7.98 vs 49.05+8.41, P 0.001), the age of admission (45.52+9.61 vs 51.91+8.71, P = 0.022), the positive family history (78.6% vs 33.3%, P = 0.015), the incidence of hypertension (8.0% vs 40.9%, P = 0.014) and the use of antihypertensive drugs (8.0% vs 40.9%, P = 0.014) had statistical significance, while the other cerebrovascular diseases (78.6% vs 33.3%, P = 0.015) had statistical significance. There was no significant difference in risk factors and past hypotension and anticoagulant use.
2. Imaging: The high signal volume (HSV) of white matter in the mutant group was significantly higher than that in the non-mutant group (70.81 44.90 vs 42.24 6550 No significant difference was found between the two groups in the detection rate of intracerebral lacunar foci and the location of their distribution (subcortical, cortical and brainstem). However, in the number of intracerebral lacunar foci (5.33 [3.96] vs 2.00 [2.45, P = 0.007], the number of intracerebral microbleeding foci, the number of intracerebral microbleeding foci and the upper cranium of MRA in the mutant group was significantly higher than that in the non-mutant group. There was no significant difference between the two groups. The MMSE score was negatively correlated with white matter hyperintense signal volume and the number of intracerebral infarcts, but not with the degree of intracerebral microhemorrhage. 3. Further analysis of the patients with NOTCH3 gene mutation with MRA intracranial large artery stenosis showed that the patients with intracranial large artery disease had CAD ASIL. The prevalence of hypercholesterolemia (62.5% vs 17.6%, P = 0.061) and hypertension (40.0% vs 0.0%, P = 0.065) were higher than that of CAD ASIL without intracranial arterial lesions, but there was no significant statistical difference because of the fewer cases. There was no statistical difference.
1. Severe leukoencephalopathy involving the temporal and basal ganglia extracapsular areas on imaging. Positive family history can be used as a useful indicator for clinical diagnosis of CADASIL. Less than 45 years of age is helpful for the diagnosis of CADASIL. Clinical manifestations (headache, stroke, mental disorders and cognitive impairment) and imaging findings include subcortical infarction, cortical infarction. Foci and intracerebral microbleeds can not be used to distinguish between NOTCH3 mutation patients and non mutation patients.
2, risk factors for cerebrovascular disease and intracranial artery stenosis can not be used as exclusion criteria for CADAS.
3. Cognitive function of CADASIL patients may be negatively correlated with high signal volume of white matter and the number of intracerebral lacunar lesions, but not with the severity of intracerebral microhemorrhage.
【學(xué)位授予單位】：浙江大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2014
【分類號】：R743.3

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1 吳雪瓊;張俊仙;李洪敏;梁建琴;鐘敏;王巍;;結(jié)核分支桿菌耐藥基因的研究[A];中國防癆協(xié)會(huì)全國學(xué)術(shù)會(huì)議大會(huì)學(xué)術(shù)報(bào)告[C];2001年

2 楊芳;金佩佩;王學(xué)鋒;丁秋蘭;王鴻利;李薇;王冠軍;;2例新的基因突變導(dǎo)致遺傳性蛋白S缺陷癥[A];第11次中國實(shí)驗(yàn)血液學(xué)會(huì)議論文匯編[C];2007年

3 馮義國;白轉(zhuǎn)麗;肖生祥;譚升順;吳佳紋;;先天性厚甲癥Ⅰ型的基因突變研究[A];中華醫(yī)學(xué)會(huì)第14次全國皮膚性病學(xué)術(shù)年會(huì)論文匯編[C];2008年

4 劉第墉;;HOX基因熱潮:又一次爆發(fā)性抄炒[A];中國古生物學(xué)會(huì)第21屆學(xué)術(shù)年會(huì)論文摘要集[C];2001年

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7 呂鶴;呼群;袁云;;中國CADASIL的臨床和基因改變規(guī)律[A];第九次全國神經(jīng)病學(xué)學(xué)術(shù)大會(huì)論文匯編[C];2006年

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2 實(shí)習(xí)生 劉冰玉;檢測癌癥基因能否一紙完成？[N];科技日報(bào);2012年

3 記者 耿建擴(kuò) 通訊員 李晉陶 程益聰;人類8種新發(fā)基因突變被發(fā)現(xiàn)[N];光明日報(bào);2013年

4 查莉 武佼芳;市中心醫(yī)院發(fā)現(xiàn)人類8種新發(fā)基因突變[N];邯鄲日報(bào);2013年

5 吳汐;英科學(xué)家發(fā)現(xiàn)語言基因[N];遼寧日報(bào);2001年

6 奇云;基因檢測預(yù)知疾病幾多風(fēng)險(xiǎn)[N];大眾科技報(bào);2007年

7 張?zhí)锟?基因的對壘與相互依存[N];大眾科技報(bào);2000年

8 馬曉燕;查一下基因，能預(yù)知你容易得啥病[N];新華每日電訊;2005年

9 本報(bào)記者 夏雄偉;我們走在國內(nèi)基因產(chǎn)業(yè)的最前列[N];證券時(shí)報(bào);2000年

10 吉吉邋編譯;科學(xué)家已發(fā)現(xiàn)吸煙基因[N];第一財(cái)經(jīng)日報(bào);2008年

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10 尹光浩;非小細(xì)胞肺癌的磷酸化EGFR與EGFR基因突變的比較分析[D];吉林大學(xué);2009年

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7 石文;中國南方漢族和西藏藏族RHCE基因多態(tài)性研究[D];廣州中醫(yī)藥大學(xué);2012年

8 呂衛(wèi)剛;家族性腺瘤性息肉病基因診斷流程的建立及三個(gè)家系的突變分析[D];中南大學(xué);2010年

9 劉曉蕾;肺癌EGFR基因突變檢測方法的建立及臨床應(yīng)用[D];遼寧醫(yī)學(xué)院;2012年

10 臧文巧;豫醫(yī)無毛小鼠無毛基因突變部位的定位和分析[D];鄭州大學(xué);2004年

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