MITF致病性突变与Waardenburg综合征临床表型相关性分析  

Correlation between MITF Pathogenic Mutations and Clinical Phenotypes

作　　者：倪晓琛 李佳楠[1,2,3,4] 杨仕明 陈伟[1,2,3,4] NI Xiaochen;LI Jianan;YANG Shiming;CHEN Wei(Senior Department of Otolaryngology-Head&Neck Surgery,the Sixth Medical Center of PLA General Hospital,Beijing 100853;National Clinical Research Center for Otolaryngologic Diseases,Beijing 100853;State Key Lab of Hearing Science,Ministry of Education,Beijing 100853;Beijing Key Lab of Hearing Impairment Prevention and Treatment,Beijing 100853)

机构地区：[1]解放军总医院第六医学中心耳鼻咽喉头颈外科医学部,北京100853 [2]国家耳鼻咽喉疾病临床医学研究中心,北京100853 [3]聋病教育部重点实验室,北京100853 [4]聋病防治北京市重点实验室,北京100853

出　　处：《中华耳科学杂志》2023年第2期211-217,共7页Chinese Journal of Otology

基　　金：国家自然科学基金面上项目(819708901011106);国家自然科学基金青年科学基金项目(820009761008986)。

摘　　要：目的本研究旨在初步探索MITF致病性突变中突变类型、突变位点与临床表型之间的关系,为基因诊断提供参考依据并进一步研究Waardenburg综合征(Waardenburg syndrome,WS)患者临床表现高度异质性的内在原因。方法以关键词“Waardenburg syndrome”、“MITF”、以及“Waardenburg综合征”进行文献检索,于PubMed数据库以及CNKI数据库检索1995年至2021年11月10日间的文献,并依据纳入以及排除标准进行文献筛选。收集并整理文献中家系成员的临床表型。同时在ClinicalVariant数据库中进行MITF致病性突变位点检索。建立MITF致病性突变位点的数据库。基于MITF蛋白结构以及功能的改变,将突变类型进一步分组。并以广义估计方程(generalized estimating equations,GEE)的分析方法,探索突变类型以及临床表型之间的相关性。结果经过文献筛选,最终纳入文献28篇,并结合ClinicalVariant数据库,建立了包含58例致病性突变位点的MITF致病性突变数据库。其中MITF致病性突变中以无义突变为主,各外显子中均可出现,而错义突变的突变位点则集中于外显子7,8,主要影响bHLH结构的编码区进而影响MITF蛋白的功能,导致疾病的出现。在突变位点以及临床表型的关系中,核定位信号结构阈的氨基酸(Amino Acid,AA)替代与虹膜异色、听力下降(P=0、P=0)具有相关性,HLH结构阈的AA替代与虹膜异色、面部雀斑、头发颜色异常、听力下降(P=0.013、P=0.025、P=0、P=0)具有相关性。通过突变类型与临床表型相关性的探索,进一步证实bHLH-Zip结构阈以及其包含的核定位信号在MITF的作用过程中的重要作用。结论MITF致病性突变中错义突变多发生于其特征性结构阈bHLH-Zip的编码区进而影响MITF的功能,最终导致疾病的出现。错义突变位于核定位信号编码区时,WS患者更易出现听力下降。Objective To investigate the relationship between the type and site of MITF pathogenic mutations and clinical phenotypes for genetic diagnosis and understanding of causes for high heterogeneity of clinical manifestations in Waardenburg syndrome(WS)patients.Methods Literatures in the PubMed and CNKI databases between 1995 and November 10,2021 were searched using key words"MITF"and"Waardenburg syndrome".From studies meeting the inclusion/exclusion criteria,clinical phenotypes of pedigree members were collected.The ClinicalVariant database was searched for MITF pathogenic mutation loci to build a MITF pathogenic mutation locus database.MITF mutation types were further grouped based on the changes of MITF proteins and functions.The correlation between mutation types and clinical phenotypes was analyzed using generalized estimating equations.Results Twenty eight studies met inclusion criteria and were included.A MITF pathogenic mutation database containing 58 pathogenic mutation loci was established based on the information from the literature search and in the ClinicalVariant database.Most MITF pathogenic mutations in the established database were nonsense mutations involving all exons.Missense mutations were concentrated in exons 7 and 8,which mainly affect the coding region of bHLH structure and subsequently MITF functions,leading to the manifestation of the disease.Regarding relations between mutation sites and clinical phenotypes,amino acid(AA)substitution in the nuclear localization signal domain was correlated with heterochromia iris and hearing loss(P=0,P=0,respectively),and AA substitution in the HLH domain was associated with heterochromia iris,freckles,hair color abnormalities and hearing loss(P=0.013,P=0.025,P=0,P=0,respectively).Conclusion From our preliminary analysis of the relationship between clinical phenotypes and MITF mutation types,missense mutations ultimately cause change of functions of the MITF protein by affecting the characteristic structural region bHLH-Zip,leading to the disease.Important

关 键 词：WAARDENBURG综合征 MITF bHLH-Zip 

分 类 号：R764[医药卫生—耳鼻咽喉科]