节段型神经纤维瘤病的临床及NF1基因突变研究
发布时间：2019-03-28 17:20
【摘要】：背景 I型神经纤维瘤病(neurofibromatosis type 1,NF1)是一种常染色体显性遗传性疾病,临床表现为皮肤牛奶咖啡斑、腋窝和腹股沟雀斑、神经纤维瘤、虹膜错构瘤(Lisch结节)、神经胶质瘤、学习障碍、癫痫和骨骼发育不良等。节段型神经纤维瘤病(segmental neurofibromatosis,SNF)是NF1的罕见类型,其临床特征表现为皮肤牛奶咖啡斑和神经纤维瘤同时或分别分布在一个或多个皮区内。NFI基因定位于人类染色体17q11.2中央区,负责编码神经纤维瘤蛋白。NF1基因是一种抑癌基因,通过神经纤维瘤蛋白对Ras进行负向调控,参与细胞生长、分化和肿瘤的发生。迄今为止,在人类基因突变数据库中查询到NFI基因突变点有2600多个,突变类型包括错义突变和无义突变、剪切突变、插入、缺失和重复,大多数突变导致了截短蛋白的表达。国内外对NF1基因进行了大量研究,不过关于NF1基因型和表型的关系尚不明确。目的分析一例以严重凸眼、半脸牛奶咖啡斑为特征的SNF患者的临床表现,并检测NF1基因,丰富NF1基因突变数据库,为NF1的遗传咨询、产前诊断、基因诊断奠定基础。再利用本研究检测结果,结合既往文献报道,探讨NF1突变及其基因型和临床表型的关系。方法对该SNF患者进行颅脑核磁共振检查(MRI)及眼科检查,获得相关影像及数据。抽取该患者及其父母的外周血,提取DNA,设计NF1所有外显子引物,通过PCR反应进行基因扩增,并进行基因测序。结果(1)临床发现:患者右侧头面部、躯干、四肢散在数个分界良好、表面光滑的牛奶咖啡斑,右眼眼球明显突出,右眼视力降低,左侧肢体伴有阵发性抽搐,出现一次癫痫持续状态。颅脑MRI示右侧颅内海绵状血管畸形伴陈旧性出血和右侧大脑半球及间脑萎缩,右眼球突出,右侧玻璃体增大变形,右侧视神经增粗。眼科检查示右眼眼压升高,诊断继发性青光眼。(2)NF1基因突变分析:直接DNA测序显示外显子13的6个点突变、外显子18的1个点突变、外显子30的1个杂合缺失突变和3'非翻译区(UTR)的2个点突变。它们分别是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之前已经报道,其余9个均为首次报道。4个错义突变包括p.Thr4671Ile、p.Asp483Gly、p.Tyr489Cys 和 p.Lys505Glu,分别由 NF1 的 mRNA中的 c.1400CT、c.1448AG、c.1466AG 和 c.1513AG 编码,经 PolyPhen 预测,这4个突变为有害突变。结论 NF1 基因的突变 c.1400CT、c.1448AG、c.1458AG、c.1461AG、c.1466AG、c.1513AG、c.2034GA、chr17:31248997-/G、chr17:31376357 GA、chr17:31376421 CG扩展了 NF1基因突变数据库,可能为该SNF患者发病的原因,并且可能与单侧头面部咖啡斑、单侧眼球突出、颅内海绵状血管畸形和单侧脑萎缩相关。
[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.
【学位授予单位】：南方医科大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R596.1
本文编号：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.
【学位授予单位】：南方医科大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R596.1
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