白质消融性白质脑病致病基因EIF2B5突变蛋白功能研究
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摘要
白质消融性白质脑病(Leukoencephalopathy with vanishing white matter,VWM,OMIM#603896)是儿童期起病的最常见遗传性白质脑病之一,该病是迄今为止已知的唯一一种由于真核细胞蛋白质翻译启动异常所导致的人类遗传病。典型的临床表现为缓慢进展的神经系统退行性变,运动倒退重于智力倒退。头颅核磁(MRI)具有区别于其它白质脑病的特异表现:弥漫对称的白质异常,T1、T2及Flair像上异常白质接近脑脊液信号,提示异常白质呈液化表现。2001~2002年发现本病致病基因是由于编码真核细胞翻译启动因子2B(Eukaryotictranslation initiation factor 2B,EIF2B)五个亚单位(EIF2Ba-ε)的相应编码基因(EIF2B1-5)之一突变所致,但对其蛋白功能研究目前尚处于起步阶段,我国对VWM患者的EIF2B1-5基因及其突变研究尚未见报道。对其发病机制的深入研究将有可能了解蛋白质翻译启动这一重要而复杂的生理过程以及对蛋白质翻译异常性疾病的共同发生机制提供重要线索。
目的:对4例临床诊断VWM患者进行EIF2B1-5基因突变分析。通过构建我们首次在中国人中发现的国际上未报道的EIF2B5基因突变功能进行研究,初步了解EIF2B5基因不同区域突变对eIF2Bε蛋白功能的影响,以推测和进一步研究该蛋白功能域的分布,为深入探讨VWM的发病机制提供了线索。
方法:对2007-2008年北京大学第一医院儿科收集的4例临床诊断VWM患者,采用聚合酶链反应(PCR)与DNA直接测序的方法进行EIF2B1~5基因突变分析。构建我们首次在中国人中发现的国际上未报道的EIF2B5基因5种突变体质粒:c.185 A>T(p.D62V),c.805C>T(p.R269X),c.1004 G>C(p.C335S),c.1126A>C(p.N376D),c.1827 1838del(p.S610_D613del),转染HEK293细胞,应用Western Blot方法测定以上5种突变对EIF2B5基因蛋白表达量的影响。
结果:4例临床诊断VWM的患者EIF2B1-5基因检测结果显示:1例患者发现EIF2B3纯合突变c.1037 T>C(p.I346T);1例EIF2B复合杂合5突变c.337 C>T(p.R113C),c.806G>A(p.R269Q)。其中c.1037 T>C(p.I346T)为未报道的错义突变c.337 C>T(p.R113C),c.806G>A(p.R269Q)为已知报道的错义突变:家系分析证实患者的突变均来自父母双方。其余2例患者未发现EIF2B1-5基因的外显子及其与内含子连接区域的改变。Western Blot方法检测EIF2B5野生型与5种突变体的EIF2B5蛋白表达结果显示:与野生型相比较,c.805C>T(p.R269X)及c.1126A>C(p.N376D)EIF2B5蛋白表达量减少,而且具有统计学意义(P<0.05),其中c.805C>T(P.R269X)突变体EIF2B5蛋白表达量减少较显著,其余3种突变体EIF2B5蛋白表达未见明显改变。。
结论:通过对4例临床诊断的VWM患者EIF2B1-5基因分析,从基因水平确诊2例。c.337 C>T(p.R113C),c.806G>A(p.R269Q)为已知错义突变,c.1037 T>C(p.I346T)是国际上未见报道的新突变。EIF2B5的突变可以影响EIF2B5蛋白表达,其中c.805C>T(p.R269X)最为明显,分布于EIF2B5不同区域的突变对EIF2B5蛋白表达的影响不同,表明位于不同结构域EIF2B5基因突变对该蛋白功能可能存在不同的机制,这是首次在中国人中发现的EIF2B5基因新突变进行的功能研究。
Functional study on EIF2B5 gene mutations in Vanlshing White Matter disease
Leukoencephalopathy with Vanishing white matter(VWM,OMIM#603896) is one of the most prevalent inherited white matter disorders in childhood,and so far its specificness lies in that the disease results from direct defects in protein translation initiation.Typical clinical manifestation of this disease is the slow progress of the nervous system degeneration and motor function is more severe than cognitive function.The features of cranial magnetic resonance imaging(MRI) are unique, which shows specificity of abnormal signal of all or almost all cerebral white matter and its replacement by cerebrospinal fluid(CSF)。This change is best shown by fluid-attenuated inversion recovery(FLAIR) images,in which abnormal white matter just have the similar signal to CSF。Since 2001-2002,people have found that VWM is caused by mutation in any of the five genes(EIF2B1,EIF2B2,EIF2B3,EIF2B4, EIF2B5)which encoding the subunits of eukaryotic translation initiation factor eIF2B(eIF2Bα、eIF2Bβ、eIF2Bγ、eIF2Bδ、eIF2Bε).Up to date,functional study about EIF2B1-5 proteins is under of start stage.There was no reported from Chinese VWM patients.The pathogenesis of this disease is in-depth study by which we will further understands of protein translation initiation of this important and complex physiological processes as well as abnormal protein translation of the common occurrence of disease mechanisms.
Objective:To analyze EIF2B1-5 gene mutations in four Chinese patients with VWM diagnoses clinically.To understand effect of EIF2B5 gene mutations in different regions of eIF2Bε,functional study about EIF2B5 mutagenesis from Chinese VWM patients was performed.This would be useful to speculate and further study the distributions of the difference EIF2B5 domains,and provide the clue for exploring pathogenesis of VWM.
Method:Four VWM patients diagnoses clinically were enrolled from Peking Univesity First Hospital in 2007-2008.All exons and exon-intron boundaries of EIF2B1-5 genes were amplified by polymerase chain reaction(PCR) and followed by direct DNA sequencing.Five mutant p.CMV-EIF2B5 for novel mutations found from Chinese VWM patients,c.185 A＞T(p.D62V),c.805C＞T(P.R269X),c.1004 G＞C (p.C335S),c.1126A＞C(p.N376D),c.l827_1838del(p.S610_D613del),were constructed by site-directed mutagenesis assays.HEK293 cells were used for transfection.Expression of EIF2B5 protein from wildtype and mutant types were detected using Western Blot methods.
Result:Sequencing results of EIF2B1-5 for four VWM patients shows:Two heterozygous mutations of EIF2B5 were identified c.337 C＞T(p.R113C) in exon3 and c.806G＞A(p.R269Q) in exon6 from patient 1.One homozygous novel mutation of EIF2B3 were identified c.1037 T＞C(p.I346T) in exon9 from patient 2.Their parents were found the heterozygous variation in those sites.The other two patients didn't find any changes from EIF2B1-5.Expression results of EIF2B5 protein by Western Blot methods demonstrated that there were decreased from mutants c.805C＞T (P.R269X) and c.1126A＞C(p.N376D) compared with wildtype.With the statistical significance,this two kinds of mutant EIF2B5 have significant change in protein expression(P＜0.05).The protein of mutants c.805C＞T(P.R269X) has more significant decrease.
Conclusion:Through analysis of EIF2B1-5 for four VWM patients diagnoses clinically,c.337 C＞T(p.R113C)、c.806G＞A(p.R269Q) and c.1037 T＞C(p.I346T) were found from two patients.The first two mutations were reported and the latter is novel mutation not reported around world yet.Expression of EIF2B5 protein decreased from mutant c.805C＞T(P.R269X) and c.1126A＞C(p.N376D) which demonstrated that there are different effects in different regions of EIF2B5 gene mutations.Thus there may have different mechanisms of EIF2B5 protein function by different domains.This is the first report about functional study of ELF2B5 mutations from VWM patients in China.
目的:对4例临床诊断VWM患者进行EIF2B1-5基因突变分析。通过构建我们首次在中国人中发现的国际上未报道的EIF2B5基因突变功能进行研究,初步了解EIF2B5基因不同区域突变对eIF2Bε蛋白功能的影响,以推测和进一步研究该蛋白功能域的分布,为深入探讨VWM的发病机制提供了线索。
方法:对2007-2008年北京大学第一医院儿科收集的4例临床诊断VWM患者,采用聚合酶链反应(PCR)与DNA直接测序的方法进行EIF2B1~5基因突变分析。构建我们首次在中国人中发现的国际上未报道的EIF2B5基因5种突变体质粒:c.185 A>T(p.D62V),c.805C>T(p.R269X),c.1004 G>C(p.C335S),c.1126A>C(p.N376D),c.1827 1838del(p.S610_D613del),转染HEK293细胞,应用Western Blot方法测定以上5种突变对EIF2B5基因蛋白表达量的影响。
结果:4例临床诊断VWM的患者EIF2B1-5基因检测结果显示:1例患者发现EIF2B3纯合突变c.1037 T>C(p.I346T);1例EIF2B复合杂合5突变c.337 C>T(p.R113C),c.806G>A(p.R269Q)。其中c.1037 T>C(p.I346T)为未报道的错义突变c.337 C>T(p.R113C),c.806G>A(p.R269Q)为已知报道的错义突变:家系分析证实患者的突变均来自父母双方。其余2例患者未发现EIF2B1-5基因的外显子及其与内含子连接区域的改变。Western Blot方法检测EIF2B5野生型与5种突变体的EIF2B5蛋白表达结果显示:与野生型相比较,c.805C>T(p.R269X)及c.1126A>C(p.N376D)EIF2B5蛋白表达量减少,而且具有统计学意义(P<0.05),其中c.805C>T(P.R269X)突变体EIF2B5蛋白表达量减少较显著,其余3种突变体EIF2B5蛋白表达未见明显改变。。
结论:通过对4例临床诊断的VWM患者EIF2B1-5基因分析,从基因水平确诊2例。c.337 C>T(p.R113C),c.806G>A(p.R269Q)为已知错义突变,c.1037 T>C(p.I346T)是国际上未见报道的新突变。EIF2B5的突变可以影响EIF2B5蛋白表达,其中c.805C>T(p.R269X)最为明显,分布于EIF2B5不同区域的突变对EIF2B5蛋白表达的影响不同,表明位于不同结构域EIF2B5基因突变对该蛋白功能可能存在不同的机制,这是首次在中国人中发现的EIF2B5基因新突变进行的功能研究。
Functional study on EIF2B5 gene mutations in Vanlshing White Matter disease
Leukoencephalopathy with Vanishing white matter(VWM,OMIM#603896) is one of the most prevalent inherited white matter disorders in childhood,and so far its specificness lies in that the disease results from direct defects in protein translation initiation.Typical clinical manifestation of this disease is the slow progress of the nervous system degeneration and motor function is more severe than cognitive function.The features of cranial magnetic resonance imaging(MRI) are unique, which shows specificity of abnormal signal of all or almost all cerebral white matter and its replacement by cerebrospinal fluid(CSF)。This change is best shown by fluid-attenuated inversion recovery(FLAIR) images,in which abnormal white matter just have the similar signal to CSF。Since 2001-2002,people have found that VWM is caused by mutation in any of the five genes(EIF2B1,EIF2B2,EIF2B3,EIF2B4, EIF2B5)which encoding the subunits of eukaryotic translation initiation factor eIF2B(eIF2Bα、eIF2Bβ、eIF2Bγ、eIF2Bδ、eIF2Bε).Up to date,functional study about EIF2B1-5 proteins is under of start stage.There was no reported from Chinese VWM patients.The pathogenesis of this disease is in-depth study by which we will further understands of protein translation initiation of this important and complex physiological processes as well as abnormal protein translation of the common occurrence of disease mechanisms.
Objective:To analyze EIF2B1-5 gene mutations in four Chinese patients with VWM diagnoses clinically.To understand effect of EIF2B5 gene mutations in different regions of eIF2Bε,functional study about EIF2B5 mutagenesis from Chinese VWM patients was performed.This would be useful to speculate and further study the distributions of the difference EIF2B5 domains,and provide the clue for exploring pathogenesis of VWM.
Method:Four VWM patients diagnoses clinically were enrolled from Peking Univesity First Hospital in 2007-2008.All exons and exon-intron boundaries of EIF2B1-5 genes were amplified by polymerase chain reaction(PCR) and followed by direct DNA sequencing.Five mutant p.CMV-EIF2B5 for novel mutations found from Chinese VWM patients,c.185 A＞T(p.D62V),c.805C＞T(P.R269X),c.1004 G＞C (p.C335S),c.1126A＞C(p.N376D),c.l827_1838del(p.S610_D613del),were constructed by site-directed mutagenesis assays.HEK293 cells were used for transfection.Expression of EIF2B5 protein from wildtype and mutant types were detected using Western Blot methods.
Result:Sequencing results of EIF2B1-5 for four VWM patients shows:Two heterozygous mutations of EIF2B5 were identified c.337 C＞T(p.R113C) in exon3 and c.806G＞A(p.R269Q) in exon6 from patient 1.One homozygous novel mutation of EIF2B3 were identified c.1037 T＞C(p.I346T) in exon9 from patient 2.Their parents were found the heterozygous variation in those sites.The other two patients didn't find any changes from EIF2B1-5.Expression results of EIF2B5 protein by Western Blot methods demonstrated that there were decreased from mutants c.805C＞T (P.R269X) and c.1126A＞C(p.N376D) compared with wildtype.With the statistical significance,this two kinds of mutant EIF2B5 have significant change in protein expression(P＜0.05).The protein of mutants c.805C＞T(P.R269X) has more significant decrease.
Conclusion:Through analysis of EIF2B1-5 for four VWM patients diagnoses clinically,c.337 C＞T(p.R113C)、c.806G＞A(p.R269Q) and c.1037 T＞C(p.I346T) were found from two patients.The first two mutations were reported and the latter is novel mutation not reported around world yet.Expression of EIF2B5 protein decreased from mutant c.805C＞T(P.R269X) and c.1126A＞C(p.N376D) which demonstrated that there are different effects in different regions of EIF2B5 gene mutations.Thus there may have different mechanisms of EIF2B5 protein function by different domains.This is the first report about functional study of ELF2B5 mutations from VWM patients in China.
引文
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[2]Brinkman RR,Dube MP,Rouleau GA,Orr AC,Samuels ME.Human monogenic disorders-a source of novel drug targets.Nat Rev Genet.2006;7(4):249-260
[3]O'Connor TP,Crystal RGGenetic medicines:treatment strategies for hereditary disorders.Nat Rev Genet.2006 Apr;7(4):261-76.
[4]吴晔,姜玉武,秦炯等.白质消融性白质脑病临床分析.中华儿科杂志,2007,45:115-120
[5]Leegwater PAJ,Vermeuden G Konst AAM,et al.Subunits of translation initiation factor eIF2B are mutant in leukoencephalopathy with vanishing white matter.Nature Genet,2001,29:383-388
[6]O.Scali,C.Di Perri,A.Federico.The spectrum of mutations for the diagnosis of vanishing white matter disease.Neurol Sci(2006)27:271-277
[7]Van der Knaap MS,van Berkel CGM,Herms J,et al.eIF2B-related Disorders:antenatal onset and involvement of multiple organs.Am J Hum Genet,2003,73:1199-1207
[8]Van der Knaap MS,Barth PG,Gabreels FJM,et al,A new leukoencephalopathy with vanishing white matter.Neurology,1997,48:845-855
[9]Van der Knaap MS,Kamphorst W,Barth PG,et al.Phenotypic variation in leukoencephalopathy with vanishing white matter.Neurology,1998,51:540-547
[10]Matsui M,Mizutani K,Miki Y,et al.Adult-onset leukoencephalopathy with vanishing white matter European Journal of Radiology Extra 46(2003)90-92
[11]Riecker A,Thomas N,Marco H,Ludger S.Late onset vanishing white matter disense J Neurol(2007)254:544-545
[12]Scheper GC,Proud CG,Van der Kannp MS.Defective translation initiation causes Vanishing of cerebral white matter.Trends Mol Med,2006,12:159-166
[13]Fogli A,Rodriguez D,Eymard-Pierre E,et al.Ovarian failure related to eukaryotic initiation factOr 2B mutations.Am J Hum Genet,2003,72:1544-1550
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[1]van der Kannp MS,Pronk JC,Scheper GC.Vanishing matter matter disease.Lancet Neurol,2006;5:413-423
[2]吴晔,姜玉武,秦炯等.白质消融性白质脑病临床分析.中华儿科杂志,2007,45:115-120
[3]Leegwater PAJ,Vermeuden G,Konst AAM,et al.Subunits of translation initiation factor eIF2B are mutant in leukoen cephalopathy with vanishing white matter.Nature Genet,2001,29:383-388.
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[2]Brinkman RR,Dube MP,Rouleau GA,Orr AC,Samuels ME.Human monogenic disorders-a source of novel drug targets.Nat Rev Genet.2006;7(4):249-260
[3]O'Connor TP,Crystal RGGenetic medicines:treatment strategies for hereditary disorders.Nat Rev Genet.2006 Apr;7(4):261-76.
[4]吴晔,姜玉武,秦炯等.白质消融性白质脑病临床分析.中华儿科杂志,2007,45:115-120
[5]Leegwater PAJ,Vermeuden G Konst AAM,et al.Subunits of translation initiation factor eIF2B are mutant in leukoencephalopathy with vanishing white matter.Nature Genet,2001,29:383-388
[6]O.Scali,C.Di Perri,A.Federico.The spectrum of mutations for the diagnosis of vanishing white matter disease.Neurol Sci(2006)27:271-277
[7]Van der Knaap MS,van Berkel CGM,Herms J,et al.eIF2B-related Disorders:antenatal onset and involvement of multiple organs.Am J Hum Genet,2003,73:1199-1207
[8]Van der Knaap MS,Barth PG,Gabreels FJM,et al,A new leukoencephalopathy with vanishing white matter.Neurology,1997,48:845-855
[9]Van der Knaap MS,Kamphorst W,Barth PG,et al.Phenotypic variation in leukoencephalopathy with vanishing white matter.Neurology,1998,51:540-547
[10]Matsui M,Mizutani K,Miki Y,et al.Adult-onset leukoencephalopathy with vanishing white matter European Journal of Radiology Extra 46(2003)90-92
[11]Riecker A,Thomas N,Marco H,Ludger S.Late onset vanishing white matter disense J Neurol(2007)254:544-545
[12]Scheper GC,Proud CG,Van der Kannp MS.Defective translation initiation causes Vanishing of cerebral white matter.Trends Mol Med,2006,12:159-166
[13]Fogli A,Rodriguez D,Eymard-Pierre E,et al.Ovarian failure related to eukaryotic initiation factOr 2B mutations.Am J Hum Genet,2003,72:1544-1550
[14]Anthony TGFabian,Kimball SR,Jefferson LS.Identification of domains within the epsilon-subunit of the translation initiation factor eIF2B that are necessary for guanine nucleotide exchance activity and eIF2B holoprotein formation.Biochim Biophys Acta.2000;1492(1):56-62
[1]van der Kannp MS,Pronk JC,Scheper GC.Vanishing matter matter disease.Lancet Neurol,2006;5:413-423
[2]吴晔,姜玉武,秦炯等.白质消融性白质脑病临床分析.中华儿科杂志,2007,45:115-120
[3]Leegwater PAJ,Vermeuden G,Konst AAM,et al.Subunits of translation initiation factor eIF2B are mutant in leukoen cephalopathy with vanishing white matter.Nature Genet,2001,29:383-388.
[4]Scheper GC,Proud CG,Van der Kannp MS.Defective translation initiation causes vanishing of cerebral white matter.Trends Mol Med,2006,12:159-166
[5]Dever TE.Gene-specific regulation by general translation factors.Cell,2002,108:545-556
[6]Pavitt GD.eIF2B,a mediator of general and gene-specific translational control.Biochem Soc Trans,2005,33:1487-1492
[7]Kubica N,Jefferson LS,Kimball SR.Eukaryotic initiation factor 2B and its role in alteration that occur under a number of pathophysiological and physiological conditions.Progress ill Nucleic Acid Research,2006,81:271-296
[8]Clemens M.J,Initiation factor eIF2a phosphorlation in stress responses and apoptosis.Prog.Mol.Subcell.Biol.2001,27,57-89
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