ABCA4基因新突变导致的Stargardt病一家系的临床特征与遗传学分析  

Clinical characteristics and genetic analysis of a pedigree with Stargardt disease caused by a novel mutation in ABCA4 gene

作　　者：王榕榕 刘静文 马婧瑜 甄庆洁 卢志明[1] 白晓卉 Wang Rongrong;Liu Jingwen;Ma Jingyu;Zhen Qingjie;Lu Zhiming;Bai Xiaohui(Department of Clinical Laboratory,Shandong Provincial Hospital,Shandong University,Jinan 250021,China;Department of Ophthalmology,the Second People′s Hospital of Jinan,Jinan 250021,China)

机构地区：[1]山东大学附属省立医院临床医学检验部,济南250021 [2]济南市第二人民医院眼科,济南250021

出　　处：《中华检验医学杂志》2022年第12期1219-1226,共8页Chinese Journal of Laboratory Medicine

基　　金：国家自然科学基金(81670942,81470704);山东省泰山学者青年专家资助项目(tsqn202103180)。

摘　　要：目的对1个Stargardt病家系进行临床特征与遗传学分析,并探讨三磷酸腺苷结合盒家族亚科A成员4(ABCA4)基因突变在Stargardt病中的致病性。方法先证者因视力下降于2021年5月就诊于济南市第二人民医院,对先证者及家系成员进行详细的眼科检查,根据Stargardt病临床诊断标准评估确诊先证者为Stargardt病。提取先证者及家系其他成员基因组DNA,对先证者DNA进行全外显子测序寻找致病的突变基因。通过PolyPhen-2、SIFT、MutationTaster等网站分析突变位点危害性,利用Sanger测序验证并确认致病突变,进行同源物种保守性分析及三维蛋白结构功能预测以分析其致病性。结果眼科检查表明先证者双眼视力下降、黄斑萎缩并伴有“牛眼征”,其他家系成员均正常。通过先证者的全外显子测序分析和家系成员及正常对照的Sanger测序验证,ABCA4基因的复合杂合突变(c.215G>A和c.6563T>C)与该家系患者表型共分离。SIFT、PolyPhen-2和MutationTaster网站预测这2个突变均有害,保守性分析和三维蛋白结构模型预测表明该突变导致蛋白的结构发生改变,影响蛋白质功能。结论ABCA4基因的复合杂合突变(c.215G>A和c.6563T>C)为该Stargardt病家系携带的致病突变。Objective To explore the clinical characteristics and genetics of a pedigree with Stargardt disease,and investigate the pathogenicity of ABCA4(ATP binding cassette subfamily A member 4)gene mutations in Stargardt disease.Methods The proband was admitted to the Second People′s Hospital of Jinan in May 2021 due to diminution of vision.The proband was diagnosed with Stargardt disease according to the clinical diagnostic criteria of Stargardt disease.Detailed ophthalmological examinations was also performed on family members of the proband.Genomic DNA were extracted from the proband and the family members,and the whole exon sequencing was performed to find pathogenic gene mutations.The hazard of mutations was analyzed by polyphen-2,SIFT and MutationTaster websites.Sanger sequencing was used to verify the mutations.Conserved analysis of homologous species and 3-dimensional(3D)molecular model of the protein were used to analyze the pathogenicity.Results Ophthalmological examinations showed reduced binocular vision,macular atrophy and"bull′s eye sign"in the proband and there was no abnormal signs and symptoms among the family members.Through whole exon sequencing analysis and Sanger sequencing verification,the compound heterozygous mutations(c.215G>A and c.6563T>C)of ABCA4 gene were co-segregated with this disease in this family.SIFT,Polyphen-2 and MutationTaster predicted that these two mutations were pathogenic.Conservative analysis and 3D molecular model of protein showed that mutations could cause changes in protein structure and affect protein function.Conclusion The compound heterozygous mutations(C.215G>A and C.6563T>C)of ABCA4 gene are the pathogenic mutations of Stargardt disease in this pedigree.

关 键 词：STARGARDT病 ATP结合盒转运子 突变 家系 遗传 

分 类 号：R774[医药卫生—眼科]