中国一先天性眼外肌纤维化综合征家系及散发病例KIF21A、PHOX2A、TUBB3、TUBB2B基因突变筛查的研究

发布时间：2018-03-13 17:34

本文选题：先天性眼外肌纤维化　切入点：KIF21A　出处：《青岛大学》2014年硕士论文　论文类型：学位论文

【摘要】：目的收集1中国先天性眼外肌纤维化综合征(Congenital fibrosis of the extraocular muscles, CFEOM)家系与7例散发病例,分析其临床表型和遗传特点,研究在该家系及散发病例中是否存在已知的致病基因KIF21A、PHOX2A/ARIX, TUBB3, TUBB2B的已知突变位点的突变,探讨不同人种中CFEOM家系及散发病例的遗传异质性。方法收集青岛大学附属医院确诊的1CFEOM家系(家系JN)2代4人及散发病例7例。对家系所有成员及散发病例进行详细眼科检查及斜视专科检查,进行临床表型分析。利用聚合酶链反应扩增已知的致病基因KIF21A、PHOX2A/ARIX、TUBB3、TUBB2B已知突变的外显子区域,对扩增产物进行测序分析,筛查是否存在已知热点的突变。对照组随机选取100名健康中国人,且无血缘关系。结果1.临床研究：本研究中CFEOM家系的患者为母子关系,均伴有双眼先天性上睑下垂,眼球运动受限,被动牵拉实验(+),及代偿头位。散发患者7例,男性5例,女性2例,其中3例固定于内斜位,2例伴有异常神经支配其中1例伴有下颌瞬目综合征。2.在家系JN的2例患者中均发现KIF21A基因2860CT错义突变,该家系中的正常者及正常对照组均不存在该突变。散发的7例患者在已知的候选基因KIF21A、 PHOX2A/ARIX、TUBB3、TUBB2B的已知突变位点处均未发现致病性突变。结论1.临床表型特征：根据临床表型及遗传学特点,家系JN为CFEOM1型家系。7例散发患者具有不同临床表型,其中CFEOM1型1例,CFEOM2型1例,CFEOM3型5例,均不伴有其他全身系统性疾病。2.遗传学特征：家系JN属于常染色体显性遗传,临床表型由KIF21A基因的第21外显子2860CT错义突变导致,KIF21A基因为该家系的致病基因。对本研究中的7例散发患者KIF21A、PHOX2A/ARIX、TUBB3、TUBB2B已知突变位点的筛查,未发现已报道的热点突变,提示该7例散发CFEOM患者的致病位点与已报道的国外人种中散发的热点突变不同,说明该疾病具有遗传异质性。
[Abstract]:Objective to investigate the phenotypic and genetic characteristics of congenital extraocular muscle fibrosis syndrome (CFEOM) in 7 sporadic Chinese patients with congenital extraocular muscle fibrosis syndrome (CFEOM). To study the mutation of known mutation sites of KIF21A PHOX2A / ARIX, TUBB3, TUBB2B in this family and sporadic cases, and to explore the genetic heterogeneity of CFEOM pedigree and sporadic cases in different ethnic groups. Methods one CFEOM pedigree (4 cases of JN)2 generation and 7 cases of sporadic cases) confirmed in the affiliated Hospital of Qingdao University was collected. All the family members and sporadic cases were examined by detailed ophthalmologic examination and strabismus examination. The exon region of known pathogenic gene PHOX2A / ARIXTUBB3TUBB2B was amplified by polymerase chain reaction (PCR), and the amplified products were sequenced. In the control group, 100 healthy Chinese were randomly selected and were not related to each other. Clinical study: in this study, the patients of CFEOM family were related to mother and child, with congenital ptosis of both eyes, limited eyeball movement, passive traction test (ptosis, and compensatory head position). There were 7 sporadic patients, 5 males and 2 females. Among them, 3 cases were fixed in the internal oblique position, 2 cases were accompanied with abnormal nerve innervation, and 1 case was accompanied by mandibular blink syndrome .2.The missense mutation of KIF21A gene 2860CT was found in 2 cases of JN. The mutation was not found in normal subjects and normal controls. No pathogenicity mutations were found in the known candidate gene KIF21A, PHOX2A / ARIXTUBB3TUBB2B. Clinical phenotypic characteristics: according to the clinical phenotypic and genetic characteristics, there were 7 cases of sporadic CFEOM1 family with different phenotypes in JN pedigree, including 1 case of CFEOM1 type and 1 case of CFE OM2 type 1 case of CFEOM3 type. Genetic characteristics: family JN belongs to autosomal dominant inheritance. The clinical phenotype was caused by missense mutation in exon 21 of KIF21A gene, which resulted in KIF21A gene being the pathogenic gene in this pedigree. In this study, no reported hot spot mutations were found in 7 sporadic patients with known mutation sites of KIF21A / ARIXT TUBB3TUBB3TUBB2B. The results suggest that the pathogenicity of the 7 sporadic CFEOM patients is different from that of the reported hot spot mutations in foreign ethnic groups, indicating that the disease is genetically heterogeneous.
【学位授予单位】：青岛大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R777.4

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