跨膜蛋白43的研究进展
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摘要
跨膜蛋白43(TMEM43)是一种在物种间高度保守、定位在内核膜及内质网中且有一个大的亲水域的核膜蛋白。临床研究及流行病学调查发现,TMEM43基因的突变可导致心律失常性右心室心肌病(ARVC)和金刚砂-德雷福斯肌营养不良(EDMD)等疾病。目前,对此病的诊断及治疗尚存在一定的困难。此外,TMEM43与其他跨膜蛋白亦存在相互作用,但其功能和相关致病机制知之甚少。就TMEM43相关疾病及其与相关蛋白之间的作用进行综述,为后期研究TMEM43的功能及疾病治疗方面提供参考和帮助。
Transmembrane protein 43 is a nuclear membrane protein that is highly conserved among species. It is located in the core membrane and endoplasmic reticulum and has a large hydrophilic domain. Epidemiological studies have found that mutations of TMEM43 can lead to arrhythmogenic right ventricular cardiomyopathy( ARVC) and Emery-Dreyfus muscular dystrophy( EDMD). At present,there are still some difficulties in the diagnosis and treatment of this disease. In addition,TMEM43 also interacts with other transmembrane proteins,but its function and related pathogenic mechanisms are poorly understood. In this review,the role of TMEM43 in related diseases and the interaction between TMEM43 and associated proteins were summarized.
Transmembrane protein 43 is a nuclear membrane protein that is highly conserved among species. It is located in the core membrane and endoplasmic reticulum and has a large hydrophilic domain. Epidemiological studies have found that mutations of TMEM43 can lead to arrhythmogenic right ventricular cardiomyopathy( ARVC) and Emery-Dreyfus muscular dystrophy( EDMD). At present,there are still some difficulties in the diagnosis and treatment of this disease. In addition,TMEM43 also interacts with other transmembrane proteins,but its function and related pathogenic mechanisms are poorly understood. In this review,the role of TMEM43 in related diseases and the interaction between TMEM43 and associated proteins were summarized.
引文
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[17]KLAUKE B,KOSSMANN S,GAERTNER A,et al.De novo desmin-mutation N116S is associated with arrhythmogenic right ventricular cardiomyopathy.Human Molecular Genetics[J].Human Molecular Genetics,2010,19(23):4595-4607.
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[19]ZHENG G,JIANG C,LI Y,et al.TMEM43-S358L mutation enhances NF-κB-TGFβsignal cascade in arrhythmogenic right ventricular dysplasia/cardiomyopathy[J].Protein Cell,2019,10(2):104-119.
[20]SIRAGAM V,CUI X,MASSE S,et al.TMEM43 mutation p.S358L alters intercalated disc protein expression and reduces conduction velocity in arrhythmogenic right ventricular cardiomyopathy[J].PLo S One,2014,9(10):1-14.
[21]MILTING H,KLAUKE B,CHRISTENSEN A H,et al.The TMEM43 Newfoundland mutation p.S358L causing ARVC-5 was imported from Europe and increases the stiffness of the cell nucleus[J].European Heart Journal,2015,36(14):872-881.
[22]HONDA T,KAN AIY,OHNO S,et al.Fetal arrhythmogenic right ventricular cardiomyopathy with double mutations in TMEM43[J].Pediatrics International,2016,58(5):409-411.
[23]STROUD M J,FANG X,ZHANG J,et al.Luma is not essential for murine cardiac development and function[J].Cardiovascular Research,2018,114(3):378-388.
[24]ASIMAKI A,TANDRI H,HAYDEN H,et al.A new diagnostic test for arrhythmogenic right ventricular cardiomyopathy[J].New England Journal of Medicine,2009,360(11):1075-1084.
[25]CAPELL B C,COLLINS F C.Human laminopathies nuclei gone genetically awry[J].Genetics,2006,7(12):940-952.
[26]LIANG W C,HIROAKI M,ETSUKO K,et al.TMEM43 mutations in Emery-dreifuss muscular dystrophy-related myopathy.Ann Neurol[J].Annals of Neurology,2011,69(6):1005-1013.
[27]KJARGAARD K,KRISTENSEN J,MOLGARD H,et al.Failure of ICD therapy in lethal arrhythmogenic right ventricular cardiomyopathy type 5 caused by the TMEM43 p.Ser358Leu mutation[J].HeartRhythm Case Reports,2016,2(3):217-222.
[28]RAJKUMAR R,SEMBRAT J C,BARBARA M,et al.Functional effects of the TMEM43 Ser358Leu mutation in the pathogenesis of arrhythmogenic right ventricular cardiomyopathy[J].BMC Medical Genetics,2012,13(21):1471-2350.
[29]MEWBORN S K,PUCKELWARTZ M J.Altered chromosomal positioning,compaction,and gene expression with a lamin A_C gene mutation[J].PLo S One,2010,5(12):1-13.
[30]WORMANA H J,BONNE G.“Laminopathies:”a wide spectrum of human diseases[J].Experimental Cell Research,2007,313(10):2121-2133.
[31]BROERS J,RAMAEKERS F,BONNE G,et al.Nuclear lamins:laminopathies and their role in premature ageing[J].Physiological Reviews,2006,86(3):967-1008.
[32]AHMAD F,SEIDMAN J G,SEIDMAN C E.The genetic basis for cardiac remodeling[J].Annual Review of Genomics and Human Genetics,2005,38(6):185-216.
[33]VERGNES L,PETERFY M,MARTIN B O,et al.Lamin B1 is required for mouse development and nuclear integrity[J].Proceedings of the National Academy of Sciences of the United States of America,2004,101(28):10428-10433.
[2]何杖群.TMEM43基因定点突变克隆构建及其功能初步分析[D].衡阳:南华大学,2011.
[3]DANIELLE G,LEMAY,DANIEL H.HWANG.Genome-wide identification of peroxisome proliferator response elements using integrated computational genomics[J].Journal of Lipid Research,2006,47(7):1583-1587.
[4]NANCY D M,KATHY A H,ANNIKA F M H,et al.Arrhythmogenic right ventricular cardiomyopathy type 5 is a fully penetrant,lethal arrhythmic disorder caused by a missense mutation in the TMEM43gene[J].American Journal of Human Genetics,2008,82(4):809-821.
[5]JIANG C,ZHU Y,ZHOU Z,et al.TMEM43/LUMA is a key signaling component mediating EGFR-induced NF-κB activation and tumor progression[J].Oncogene,2016,36(20):2813-2823.
[6]GASTEIGER E,GATTIKER A,HOOGLAND C,et al.The proteomics server for in-depth protein knowledge and analysis[J].Nucleic Acids Research,2003,31(13):3784-3788.
[7]SCHIRMER E C,FLORENS L,GUAN T,et al.Nuclear membrane proteins with potential disease links found by subtractive proteomics[J].Science,2003,301(5638):1380-1382.
[8]FRANK I M,WILLIAM J M,DUANE S,et al.Diagnosis of arrhythmogenic right ventricular cardiomyopathy dyplasia[J].European Heart Journal,2010,31(7):806-814.
[9]YING L,VINCENT H S C,SHOU W N.LUMA in cardiac development and function[J].Cardiovascular Research,2018,114(3):347-348.
[10]LI K H C,BAZOUKIS G,LIU T,et al.Arrhythmogenic right ventricular cardiomyopathy/dysplasia(ARVC/D)in clinical practice[J].Journal of Arrhythmia,2017,34(1):11-12.
[11]于玮,陈东,方微致,等.心律失常性右心室心肌病13例临床病理特征分析[J].心肺血管病杂志,2017,36(12):974-978.
[12]VAN DER ZWAAG P A,JONGBLOED J D,VAN DEN BERG MP,et al.A genetic variants database for arrhythmogenic right ventricular dysplasia/cardiomyopathy[J].Human Mutation,2009,30(9):1278-1283.
[13]RAMPAZZO A.Regulatory mutations in transforming growth factor-β3 gene cause arrhythmogenic right ventricular cardiomyopathy type1[J].Cardiovascular Research,2012,96(2):366-373.
[14]FRANKE W W,DORFLINGER Y,KUHN C,et al.Protein LUMAis a cytoplasmic plaque constituent of various epithelial adherens junctions and composite junctions of myocardial intercalated disks:a unifying finding for cell biology and cardiology[J].Cell Tissue Research,2014,357(1):159-172.
[15]ABDELWAHAB A,GARDNER M,PARKASH R,et al.Ventricular tachycardia ablation in arrhythmogenic right ventricular cardiomyopathy patients with TMEM43 gene mutations[J].Journal of Cardiovascular Electrophysiology,2018,29(1):90-97.
[16]HAYWOOD A F,MERNER N D,HODGKINSON K A,et al.Recurrent missense mutations in TMEM43(ARVD5)due to founder effects cause arrhythmogenic cardiomyopathies in the UK and Canada[J].European Heart Journal,2013,34(13):1002-1011.
[17]KLAUKE B,KOSSMANN S,GAERTNER A,et al.De novo desmin-mutation N116S is associated with arrhythmogenic right ventricular cardiomyopathy.Human Molecular Genetics[J].Human Molecular Genetics,2010,19(23):4595-4607.
[18]CHRISTENSEN A H,ANDERSEN C B,TYBJARG-HANSEN A,et al.Mutation analysis and evaluation of the cardiac localization of TMEM43 in arrhythmogenic right ventricular cardiomyopathy[J].Clinical Genetics,2011,80(3):256-264.
[19]ZHENG G,JIANG C,LI Y,et al.TMEM43-S358L mutation enhances NF-κB-TGFβsignal cascade in arrhythmogenic right ventricular dysplasia/cardiomyopathy[J].Protein Cell,2019,10(2):104-119.
[20]SIRAGAM V,CUI X,MASSE S,et al.TMEM43 mutation p.S358L alters intercalated disc protein expression and reduces conduction velocity in arrhythmogenic right ventricular cardiomyopathy[J].PLo S One,2014,9(10):1-14.
[21]MILTING H,KLAUKE B,CHRISTENSEN A H,et al.The TMEM43 Newfoundland mutation p.S358L causing ARVC-5 was imported from Europe and increases the stiffness of the cell nucleus[J].European Heart Journal,2015,36(14):872-881.
[22]HONDA T,KAN AIY,OHNO S,et al.Fetal arrhythmogenic right ventricular cardiomyopathy with double mutations in TMEM43[J].Pediatrics International,2016,58(5):409-411.
[23]STROUD M J,FANG X,ZHANG J,et al.Luma is not essential for murine cardiac development and function[J].Cardiovascular Research,2018,114(3):378-388.
[24]ASIMAKI A,TANDRI H,HAYDEN H,et al.A new diagnostic test for arrhythmogenic right ventricular cardiomyopathy[J].New England Journal of Medicine,2009,360(11):1075-1084.
[25]CAPELL B C,COLLINS F C.Human laminopathies nuclei gone genetically awry[J].Genetics,2006,7(12):940-952.
[26]LIANG W C,HIROAKI M,ETSUKO K,et al.TMEM43 mutations in Emery-dreifuss muscular dystrophy-related myopathy.Ann Neurol[J].Annals of Neurology,2011,69(6):1005-1013.
[27]KJARGAARD K,KRISTENSEN J,MOLGARD H,et al.Failure of ICD therapy in lethal arrhythmogenic right ventricular cardiomyopathy type 5 caused by the TMEM43 p.Ser358Leu mutation[J].HeartRhythm Case Reports,2016,2(3):217-222.
[28]RAJKUMAR R,SEMBRAT J C,BARBARA M,et al.Functional effects of the TMEM43 Ser358Leu mutation in the pathogenesis of arrhythmogenic right ventricular cardiomyopathy[J].BMC Medical Genetics,2012,13(21):1471-2350.
[29]MEWBORN S K,PUCKELWARTZ M J.Altered chromosomal positioning,compaction,and gene expression with a lamin A_C gene mutation[J].PLo S One,2010,5(12):1-13.
[30]WORMANA H J,BONNE G.“Laminopathies:”a wide spectrum of human diseases[J].Experimental Cell Research,2007,313(10):2121-2133.
[31]BROERS J,RAMAEKERS F,BONNE G,et al.Nuclear lamins:laminopathies and their role in premature ageing[J].Physiological Reviews,2006,86(3):967-1008.
[32]AHMAD F,SEIDMAN J G,SEIDMAN C E.The genetic basis for cardiac remodeling[J].Annual Review of Genomics and Human Genetics,2005,38(6):185-216.
[33]VERGNES L,PETERFY M,MARTIN B O,et al.Lamin B1 is required for mouse development and nuclear integrity[J].Proceedings of the National Academy of Sciences of the United States of America,2004,101(28):10428-10433.