CAJ | 학술논문

背景研究发现,转化生长因子β诱导(TGFβⅠ)基因是角膜营养不良最常见的致病基因,但TGFβⅠ基因突变与患者表型的关系研究目前仍然很少. 目的探讨一个中国汉族Avellino角膜营养不良(ACD)家系的临床特征及致病原因,分析TGFβⅠ基因突变与患者表型的关系. 方法收集一个中国汉族ACD家系共3代19名家系成员,对现存活的5例患者和13名表型正常成员进行研究,采用裂隙灯显微镜、眼前节OCT、激光扫描共焦显微镜等检查方法观察受检者角膜病变的临床特点.收集所有受检者外周静脉血各2 ml,对TGFβⅠ基因进行突变分析和DNA测序.结果先证者诊断为ACD,该家系共6例患者,已去世1例,3代家系中每代均有患病者,男女患病概率相等,遗传模式符合常染色体显性遗传.该家系中3例女性患者角膜混浊病灶的形态呈面包屑样、条索样和点片状,而2例男性患者角膜混浊呈点状;女性患者角膜病变范围大于男性患者;家系中女性患者的视力为0.4～0.9,男性患者视力均为1.0.女性患者和男性患者激光扫描共焦显微镜下和眼前节OCT检查结果均无明显差别.所有患者TGFβⅠ基因中发现第4外显子的c.372G＞A(p.R124H)杂合突变(碱基G＞A),导致第124位的精氨酸变成组氨酸,并发现TGFβⅠ基因8号和12号外显子两个位点存在同义单核苷酸多态性(SNP)(c.981G＞A,V327V和c.1626T＞C,F542F),而家系中表型正常成员未发现此类改变.结论 TGFβⅠ基因的R124H突变为该ACD家系的致病突变,该家系中女性患者表型重于男性患者,未发现其与DNA测序结果相关.
배경 연구발현,전화생장인자β유도(TGFβⅠ)기인시각막영양불량최상견적치병기인,단TGFβⅠ기인돌변여환자표형적관계연구목전잉연흔소. 목적 탐토일개중국한족Avellino각막영양불량(ACD)가계적림상특정급치병원인,분석TGFβⅠ기인돌변여환자표형적관계. 방법 수집일개중국한족ACD가계공3대19명가계성원,대현존활적5례환자화13명표형정상성원진행연구,채용렬극등현미경、안전절OCT、격광소묘공초현미경등검사방법관찰수검자각막병변적림상특점.수집소유수검자외주정맥혈각2 ml,대TGFβⅠ기인진행돌변분석화DNA측서.결과 선증자진단위ACD,해가계공6례환자,이거세1례,3대가계중매대균유환병자,남녀환병개솔상등,유전모식부합상염색체현성유전.해가계중3례녀성환자각막혼탁병조적형태정면포설양、조색양화점편상,이2례남성환자각막혼탁정점상;녀성환자각막병변범위대우남성환자;가계중녀성환자적시력위0.4～0.9,남성환자시력균위1.0.녀성환자화남성환자격광소묘공초현미경하화안전절OCT검사결과균무명현차별.소유환자TGFβⅠ기인중발현제4외현자적c.372G＞A(p.R124H)잡합돌변(감기G＞A),도치제124위적정안산변성조안산,병발현TGFβⅠ기인8호화12호외현자량개위점존재동의단핵감산다태성(SNP)(c.981G＞A,V327V화c.1626T＞C,F542F),이가계중표형정상성원미발현차류개변.결론 TGFβⅠ기인적R124H돌변위해ACD가계적치병돌변,해가계중녀성환자표형중우남성환자,미발현기여DNA측서결과상관.
Background Previous studies demonstrated that the transforming growth factor beta induced (TGFβⅠ) gene is the most common disease-causing gene for corneal dystrophy.However,if DNA variant is associated with phenotype is unclear.Objective This study was to identify the clinical features and molecular genetics of a Chinese family with Avellino corneal dystrophy (ACD) and analyze the association between TGFβⅠ mutation and phenotype.Methods This study complied with Helsinki Declaration and was approved by Ethic Commission of Shenzhen Eye Hospital.Informed consent was obtained from each individual prior to any medical examination.A Chinese ACD family was collected with 19 members of 3 generations.The corneas were clinically examined by slit lamp microscope,ocular anterior segment opitical coherence tomography (OCT) and laser scanning confocal microscope in 5 affected members and 13 unaffected subjects.The peripheral blood sample of 2 ml was collected for the TGFβⅠ mutation analysis (17 exons) and DNA sequencing.Results The proband was diagnosed as ACD.Total 6 patients were found in the pedigree,and 1 male patient dead.This family accorded with an autosomal dominant in heritance pattern.The morphology of corneal opacification showed the bread crumbs-like,stripes-like and patchy-like,and that of male patients was dots-like.The lesion size was larger in female patients than that in male patients.The visual acuity was 0.4-0.9 in female patients and 1.0 in male patients.The findings of OCT and laser scanning confocal microscope were similar between the female and male patients.Sequencing of TGFBI gene revealed a heterozygous transition (c.372 G＞A) in exon 4,which resulted in Arg124His (R124H) being co-segregated with the disease in affected family members,but not in the unaffected members.The single nucleotide polymorphism (SNP) also was seen in exon 8 and 12 (c.981G＞A,V327V and c.1626T＞C,F542F) in affected members.No these variants were detected in the unaffected family members.Conclusions This study confirms that a G ＞ A transition in Arg124His of TGFBI is responsible for the pathogenesis of the Chinese ACD pedigree.The phenotype of female patients appears to be worse than that of the male patients.There is no certain evidence to verify the association between the genotype and phenotype.