節(jié)段型神經(jīng)纖維瘤病的臨床及NF1基因突變研究
發(fā)布時(shí)間：2019-03-28 17:20
【摘要】：背景 I型神經(jīng)纖維瘤病(neurofibromatosis type 1,NF1)是一種常染色體顯性遺傳性疾病,臨床表現(xiàn)為皮膚牛奶咖啡斑、腋窩和腹股溝雀斑、神經(jīng)纖維瘤、虹膜錯(cuò)構(gòu)瘤(Lisch結(jié)節(jié))、神經(jīng)膠質(zhì)瘤、學(xué)習(xí)障礙、癲癇和骨骼發(fā)育不良等。節(jié)段型神經(jīng)纖維瘤病(segmental neurofibromatosis,SNF)是NF1的罕見類型,其臨床特征表現(xiàn)為皮膚牛奶咖啡斑和神經(jīng)纖維瘤同時(shí)或分別分布在一個(gè)或多個(gè)皮區(qū)內(nèi)。NFI基因定位于人類染色體17q11.2中央?yún)^(qū),負(fù)責(zé)編碼神經(jīng)纖維瘤蛋白。NF1基因是一種抑癌基因,通過神經(jīng)纖維瘤蛋白對(duì)Ras進(jìn)行負(fù)向調(diào)控,參與細(xì)胞生長、分化和腫瘤的發(fā)生。迄今為止,在人類基因突變數(shù)據(jù)庫中查詢到NFI基因突變點(diǎn)有2600多個(gè),突變類型包括錯(cuò)義突變和無義突變、剪切突變、插入、缺失和重復(fù),大多數(shù)突變導(dǎo)致了截短蛋白的表達(dá)。國內(nèi)外對(duì)NF1基因進(jìn)行了大量研究,不過關(guān)于NF1基因型和表型的關(guān)系尚不明確。目的分析一例以嚴(yán)重凸眼、半臉牛奶咖啡斑為特征的SNF患者的臨床表現(xiàn),并檢測(cè)NF1基因,豐富NF1基因突變數(shù)據(jù)庫,為NF1的遺傳咨詢、產(chǎn)前診斷、基因診斷奠定基礎(chǔ)。再利用本研究檢測(cè)結(jié)果,結(jié)合既往文獻(xiàn)報(bào)道,探討NF1突變及其基因型和臨床表型的關(guān)系。方法對(duì)該SNF患者進(jìn)行顱腦核磁共振檢查(MRI)及眼科檢查,獲得相關(guān)影像及數(shù)據(jù)。抽取該患者及其父母的外周血,提取DNA,設(shè)計(jì)NF1所有外顯子引物,通過PCR反應(yīng)進(jìn)行基因擴(kuò)增,并進(jìn)行基因測(cè)序。結(jié)果(1)臨床發(fā)現(xiàn):患者右側(cè)頭面部、軀干、四肢散在數(shù)個(gè)分界良好、表面光滑的牛奶咖啡斑,右眼眼球明顯突出,右眼視力降低,左側(cè)肢體伴有陣發(fā)性抽搐,出現(xiàn)一次癲癇持續(xù)狀態(tài)。顱腦MRI示右側(cè)顱內(nèi)海綿狀血管畸形伴陳舊性出血和右側(cè)大腦半球及間腦萎縮,右眼球突出,右側(cè)玻璃體增大變形,右側(cè)視神經(jīng)增粗。眼科檢查示右眼眼壓升高,診斷繼發(fā)性青光眼。(2)NF1基因突變分析:直接DNA測(cè)序顯示外顯子13的6個(gè)點(diǎn)突變、外顯子18的1個(gè)點(diǎn)突變、外顯子30的1個(gè)雜合缺失突變和3'非翻譯區(qū)(UTR)的2個(gè)點(diǎn)突變。它們分別是c.1400CT、c.1448AG、c.1458AG、c.1461AG、c.1466AG、c.1513AG、c.2034GA、chr17:31248997-/G、chr17:31376357 GA、chr17:31376421 CG。除外c.1466AG之前已經(jīng)報(bào)道,其余9個(gè)均為首次報(bào)道。4個(gè)錯(cuò)義突變包括p.Thr4671Ile、p.Asp483Gly、p.Tyr489Cys 和 p.Lys505Glu,分別由 NF1 的 mRNA中的 c.1400CT、c.1448AG、c.1466AG 和 c.1513AG 編碼,經(jīng) PolyPhen 預(yù)測(cè),這4個(gè)突變?yōu)橛泻ν蛔�。結(jié)論 NF1 基因的突變 c.1400CT、c.1448AG、c.1458AG、c.1461AG、c.1466AG、c.1513AG、c.2034GA、chr17:31248997-/G、chr17:31376357 GA、chr17:31376421 CG擴(kuò)展了 NF1基因突變數(shù)據(jù)庫,可能為該SNF患者發(fā)病的原因,并且可能與單側(cè)頭面部咖啡斑、單側(cè)眼球突出、顱內(nèi)海綿狀血管畸形和單側(cè)腦萎縮相關(guān)。
[Abstract]:Background Type I neurofibromatosis (neurofibromatosis type-1, NF1) is an autosomal dominant genetic disease with clinical manifestations of skin milk coffee spots, axillary and groin freckles, neurofibromas, iris hamartoma (Lisch nodules) and gliomas. Learning disabilities, epilepsy and skeletal dysplasia, etc. Segmental neurofibromatosis (segmental neurofibromatosis,SNF) is a rare type of NF1. Its clinical features are that the skin milk coffee spot and neurofibroma are distributed in one or more skin regions at the same time or separately. The NFI gene is located in the central region of the human chromosome 17q11.2. NF1 gene is a kind of tumor suppressor gene, which negatively regulates Ras through neurofibroma protein and participates in cell growth, differentiation and tumorigenesis. Up to now, more than 2600 mutation points of NFI gene have been found in the human gene mutation database. The types of mutations include missense mutation and nonsense mutation, splicing mutation, insertion, deletion and repetition. Most of the mutations lead to the expression of truncated proteins. A large number of studies on NF1 gene have been carried out at home and abroad, but the relationship between NF1 genotype and phenotype is still unclear. Aim to analyze the clinical manifestations of a SNF patient with severe bulge and half face milk coffee spot, and to detect NF1 gene and enrich the database of NF1 gene mutation, so as to lay a foundation for genetic consultation, prenatal diagnosis and gene diagnosis of NF1. The results of this study were used to explore the relationship between NF1 mutation, genotype and clinical phenotype. Methods brain magnetic resonance imaging (MRI) and ophthalmological examination were performed in the patients with SNF, and the related images and data were obtained. The peripheral blood of the patient and his parents were extracted and DNA, was used to design all the primers of NF1 exons. The gene was amplified by PCR reaction and sequenced. Results (1) Clinical findings: the right head, face, trunk and extremities of the patients were scattered in several milk coffee spots with smooth surface, prominent eyeballs in the right eye, decreased vision in the right eye, and paroxysmal convulsions in the left limbs. A status epilepticus occurred. Brain MRI showed right intracranial cavernous vascular malformation with old hemorrhage, right cerebral hemispheric and diencephalic atrophy, right exophthalmos, right vitreous enlargement and deformation, and right optic nerve thickening. Eye examination showed elevated IOP in right eye and diagnosis of secondary glaucoma. (2) NF1 gene mutation analysis: direct DNA sequencing showed 6 point mutations in exon 13 and 1 point mutation in exon 18. One heterozygous deletion mutation in exon 30 and two point mutations in 3 'untranslated region (UTR) were found. They are c. 1400 CT, c. 1448 AG, c. 1458 AG, c. 1461 AGG, c. 1466 AGG, c. 1513 AGG, c. 2034GA, chr17 / 31248997g, chr17 / 31376357 GA,chr17:31376421 CG., respectively. 4 missense mutations including p. Thr4671Ile, p. Asp483 Glyp, p. Tyr489Cys and p. Lys505Glu. encoded by c. 1400 CT, c. 1448 AG, c. 1466 AG and c.1513AG in NF1's mRNA, respectively. These four mutations were predicted by PolyPhen to be harmful mutations. Conclusion the mutation of NF1 gene c. 1400 CT, c. 1448 AG, c. 1458 AG, c. 1461 AG, c. 1466 AG, c. 1513 AG, c. 2034 GA, chr1731248997G, chr17, 31376357 GA,chr17:31376421 CG expanded the NF1 gene mutation database, which may be the cause of SNF. It may be associated with unilateral Coffee spot, unilateral exophthalmos, intracranial cavernous vascular malformation and unilateral brain atrophy.
【學(xué)位授予單位】：南方醫(yī)科大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R596.1
本文編號(hào)：2449071
[Abstract]:Background Type I neurofibromatosis (neurofibromatosis type-1, NF1) is an autosomal dominant genetic disease with clinical manifestations of skin milk coffee spots, axillary and groin freckles, neurofibromas, iris hamartoma (Lisch nodules) and gliomas. Learning disabilities, epilepsy and skeletal dysplasia, etc. Segmental neurofibromatosis (segmental neurofibromatosis,SNF) is a rare type of NF1. Its clinical features are that the skin milk coffee spot and neurofibroma are distributed in one or more skin regions at the same time or separately. The NFI gene is located in the central region of the human chromosome 17q11.2. NF1 gene is a kind of tumor suppressor gene, which negatively regulates Ras through neurofibroma protein and participates in cell growth, differentiation and tumorigenesis. Up to now, more than 2600 mutation points of NFI gene have been found in the human gene mutation database. The types of mutations include missense mutation and nonsense mutation, splicing mutation, insertion, deletion and repetition. Most of the mutations lead to the expression of truncated proteins. A large number of studies on NF1 gene have been carried out at home and abroad, but the relationship between NF1 genotype and phenotype is still unclear. Aim to analyze the clinical manifestations of a SNF patient with severe bulge and half face milk coffee spot, and to detect NF1 gene and enrich the database of NF1 gene mutation, so as to lay a foundation for genetic consultation, prenatal diagnosis and gene diagnosis of NF1. The results of this study were used to explore the relationship between NF1 mutation, genotype and clinical phenotype. Methods brain magnetic resonance imaging (MRI) and ophthalmological examination were performed in the patients with SNF, and the related images and data were obtained. The peripheral blood of the patient and his parents were extracted and DNA, was used to design all the primers of NF1 exons. The gene was amplified by PCR reaction and sequenced. Results (1) Clinical findings: the right head, face, trunk and extremities of the patients were scattered in several milk coffee spots with smooth surface, prominent eyeballs in the right eye, decreased vision in the right eye, and paroxysmal convulsions in the left limbs. A status epilepticus occurred. Brain MRI showed right intracranial cavernous vascular malformation with old hemorrhage, right cerebral hemispheric and diencephalic atrophy, right exophthalmos, right vitreous enlargement and deformation, and right optic nerve thickening. Eye examination showed elevated IOP in right eye and diagnosis of secondary glaucoma. (2) NF1 gene mutation analysis: direct DNA sequencing showed 6 point mutations in exon 13 and 1 point mutation in exon 18. One heterozygous deletion mutation in exon 30 and two point mutations in 3 'untranslated region (UTR) were found. They are c. 1400 CT, c. 1448 AG, c. 1458 AG, c. 1461 AGG, c. 1466 AGG, c. 1513 AGG, c. 2034GA, chr17 / 31248997g, chr17 / 31376357 GA,chr17:31376421 CG., respectively. 4 missense mutations including p. Thr4671Ile, p. Asp483 Glyp, p. Tyr489Cys and p. Lys505Glu. encoded by c. 1400 CT, c. 1448 AG, c. 1466 AG and c.1513AG in NF1's mRNA, respectively. These four mutations were predicted by PolyPhen to be harmful mutations. Conclusion the mutation of NF1 gene c. 1400 CT, c. 1448 AG, c. 1458 AG, c. 1461 AG, c. 1466 AG, c. 1513 AG, c. 2034 GA, chr1731248997G, chr17, 31376357 GA,chr17:31376421 CG expanded the NF1 gene mutation database, which may be the cause of SNF. It may be associated with unilateral Coffee spot, unilateral exophthalmos, intracranial cavernous vascular malformation and unilateral brain atrophy.
【學(xué)位授予單位】：南方醫(yī)科大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R596.1
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