老年人间质性肺疾病三磷酸腺苷结合盒转运子A3基因变异筛查  

Genetic screening of adenosine triphosphate-binding cassette transporter A3 gene variants in elderly patients with interstitial lung diseases

作　　者：柳律 刘纪实[2] 盛月 范亮亮[3] 彭红[1] 罗红[1] Liu Lyu;Liu Jishi;Sheng Yue;Fan Liangliang;Peng Hong;Luo Hong(Department of Respiratory and Critical Care Medicine,Diagnosis and Treatment Center of Respiratory Disease,Second Xiangya Hospital,Central South University,Changsha 410011,China;Department of Nephrology,Third Xiangya Hospital,Central South University,Changsha 410013,China;Department of Cell Biology,College of Life Sciences,Central South University,Changsha 410013,China)

机构地区：[1]中南大学湘雅二医院呼吸与危重病医学科,长沙410011 [2]中南大学湘雅三医院肾内科,长沙410013 [3]中南大学生命科学学院细胞生物学系,长沙410013

出　　处：《中华老年医学杂志》2023年第8期927-931,共5页Chinese Journal of Geriatrics

基　　金：国家自然科学基金(82000079);湖南省自然科学基金(2021JJ40849);长沙市自然科学基金(kq2014233);中南大学研究生自由探索创新训练项目(2021zzts0570)。

摘　　要：目的筛查老年间质性肺疾病(ILDs)患者中三磷酸腺苷结合盒转运子A3(ABCA3)基因突变情况,分析老年ILDs患者的临床特征。方法回顾性研究,对2015年9月至2018年12月在中南大学湘雅二医院呼吸与危重症医学科诊断为ILDs的老年患者(≥60岁)进行影像学分析筛选后,对其中愿意提供外周血标本且签署知情同意书的103例患者进行外周血DNA提取,进行全外显子测序,筛查ABCA3基因的突变情况,并对患者的临床资料进行总结归纳。结果在6例患者中鉴定到ABCA3基因的7个罕见变异,这6例患者平均年龄为67岁(6072岁),性别分布相当,吸烟者占33.3%(2/6),其肺功能主要表现为弥散功能受损,最终诊断包括特发性肺纤维化(3/6)、非特异性间质性肺炎(1/6)和IgG4相关肺病(2/6)。同时,在其中1例患者中首次鉴定到导致特发性肺纤维化的ABCA3基因的复合杂合突变:p.Asp1465Asn、p.Leu39Val和p.Val93le3。结论ABCA3变异相关老年人ILDs具有可变性,即发病年龄、临床表现、诊断、预后在不同患者表现不同。引发早发型ILDs的ABCA3突变多为纯合子或复合杂合子,且多为致病性更强的无义突变,而引起老年人ILDs的ABCA3突变多为杂合子错义突变,这可能是引起ABCA3变异相关的老年人ILDs可变性的原因。由于目前已知治疗方案对ABCA3变异导致的ILDs患者反应欠佳,早期遗传学诊断可能通过加强疾病认知等方面使患者获益。Objective To screen mutations of the adenosine triphosphate(ATP)-binding cassette transporter A3(ABCA3)gene in elderly Chinese individuals with lung interstitial diseases(ILDs)and to analyze the clinical characteristics of ILDs in elderly patients.Methods A prospective study,After further image analysis of patients diagnosed with interstitial lung diseases between September 2015 and December 2018 at the Department of Respiratory and Critical Care Medicine,the Second Xiangya Hospital of Central South University,103 patients were willing to provide peripheral blood samples and signed informed consent.DNA samples were extracted and whole exome sequencing was performed to screen ABCA3 gene mutations.Clinical data of patients were summarized and analyzed.Results Seven rare variants of the ABCA3 gene were identified in 6 patients,with a mean age of 67 years(69-73 years)and an equal sex distribution,and 33.3%(2/6)were smokers.The most notable presentation was dffuse lung lesions.Patients final diagnoses included idiopathic pulmonary fibrosis(IPF,3/6),nonspecific interstitial pneumonia(NSIP,1/6),and IgG4-related lung disease(2/6).Meanwhile,compound heterozygous mutations of the ABCA3 gene responsible for IPF were identified in patient No.39,including p.Aspl465Asn,p.Leu3Vval and p.Val93lle3,a new finding in patients with ILDs.Conclusions ABCA3 mutation-related lung interstitial diseases exhibit variable characteristics,with differences in the age of onset,clinical manifestations,imaging features and prognosisbetweenpatients.ABCA3mutations responsible for early-onset ILDs aremostly homozygous or compound heterozygous and usually highly pathogenic nonsense mutations.In contrast,ABCA3 mutations identified in elderly patients with ILDs are often missense mutations,a possible explanation for the variability of ILDs in the elderly.Since patients with ILDs caused by ABCA3 variants respond poorly to currently available treatment options,early genetic diagnosis may benefit patients by enhancing disease awareness.

关 键 词：肺疾病 间质性 月肺表面活性物质相关蛋白质类 基因突变 

分 类 号：R563[医药卫生—呼吸系统]