Fechtner综合征的临床及分子机制研究
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摘要
Fechtner综合征是一种常染色体显性遗传的巨大血小病,其临床表现为血小板巨大,血小板减少和中性粒细胞包涵体,肾小球肾炎和/或听力丧失、白内障。非肌性肌球蛋白重链9基因(MYH9)基因突变是导致Fechtner综合征发病的分子机制。MYH9编码非肌性肌球蛋白重链ⅡA(NMMHC-ⅡA),非肌性肌球蛋白ⅡA表达于多种细胞和组织,它参与了多种细胞的功能包括细胞质分裂、细胞运动和维持细胞的形态。大多数细胞都可表达非肌性肌球蛋白重链的三种亚型ⅡA、ⅡB和ⅡC,如肾脏、耳蜗和晶状体,而中性粒细胞和血小板只表达NMMHC-ⅡA。至今为止,对Fechtner综合征的发病机制及非肌性肌球蛋白ⅡA的功能了解较少。我们诊断了国内首例遗传性Fechtner综合征家系并对其进行了临床特征和分子诊断、肾脏病变的机理和非肌性肌球蛋白ⅡA功能等方面的研究。上述研究对深入认识MYH9综合征的发病机理和非肌性肌球蛋白ⅡA的功能有重要意义。
目的:对1例遗传性Fechtner综合征家系进行临床特征和分子诊断、肾脏病变的机理和非肌性肌球蛋白ⅡA功能等方面的研究。以期初步阐明Fechtner综合征发病的分子机制。
方法:1.外周血片观察血小板和中性粒细胞形态,提取Fechtner综合征家系先证者及其家系成员外周血基因组DNA,PCR法扩增其MYH9基因所有40个外显子和侧翼序列,DNA序列分析确定MYH9基因异常。2.透射电镜观察Fechtner综合征先证者血小板和中性粒细胞的超微结构。3.间接免疫荧光方法结合DAPI复染细胞核的技术观察中性粒细胞包涵体的形态。4.HE染色、免疫组化、免疫荧光和电镜对Fechtner综合征患者的肾脏病变进行了研究。5.半定量Western-Blot检测中性粒细胞非肌性肌球蛋白ⅡA的表达。以人胚肾细胞(HEK-293)为研究对象对ⅡA、ⅡB之间的相互作用进行了探讨。RT-PCR法检测HEK-293细胞中非肌性肌球蛋白ⅡA、ⅡB的表达,并对其进行了免疫共沉淀的研究。
结果:1.外周血片可见巨大血小板,其中中等大(4-7μm)血小板占血小板的53%,巨大血小板(＞7μm)占9%。中性粒细胞胞浆中出现小的、灰蓝色的包涵体。约74%的中性粒细胞可见到中性粒细胞包涵体。PCR产物多次直接测序,均在先证者的MYH9基因外显子40中发现第5981位核苷酸由C→T杂合性突变,使第1933位密码子(CGA,编码Arg)突变为终止密码TGA。2.先证者的血小板体积大,致密颗粒、线粒体等颗粒的数量未见异常。开放管道系统基本正常。中性粒细胞形态大体正常,但胞浆中存在小的包涵体,不同于其它颗粒或细胞器并且周围无膜分隔。放大电镜倍数后发现包涵体内为致密结构,包含一些粗面内质网并且无颗粒。3.正常对照中性粒细胞胞浆中非肌性肌球蛋白ⅡA呈分散均质性分布,无绿色荧光聚集现象。而先证者及家系其他患者中性粒细胞胞浆中均可见明显团块状、半月形的绿色荧光聚集,其大小、位置与瑞氏染色的中性粒细胞包涵体相同。4.患者肾脏标本HE染色发现在12个肾小球中有6个已明显硬化,其余肾小球的部分节段系膜细胞轻.中度增生伴基质增多,并有少数节段与球囊壁粘连。间质炎症细胞小灶性分布,主要围绕在硬化肾小球周围,少数肾小管有蛋白管型。局灶性肾小管上皮细胞肿胀,颗粒变性。肾脏免疫组化观察到非肌性肌球蛋白ⅡA主要位于肾小球脏层上皮细胞(足细胞)和远曲小管上皮,微弱表达于近曲小管刷状缘。与正常肾组织相比,Fechmer综合征患者非肌性肌球蛋白HA在肾小球足细胞的表达减少,非肌性肌球蛋白ⅡA在远曲小管的表达与正常无差别。肾脏免疫荧光提示患者非肌性肌球蛋白ⅡA在肾小球的绿色荧光强度明显高于正常人,通过足细胞特异性抗体染色分析,非肌性肌球蛋白ⅡA主要沉积在肾小球足细胞,并且系膜细胞和系膜基质轻度增生。患者肾脏标本电镜显示2个肾小球,其中1个已发生硬化,另1个为节段性硬化。肾小球系膜区有中度电子致密物沉积,伴有局部系膜细胞增生及基质增多。足突部分融合伴少量微绒毛形成。5.免疫印迹显示先证者中性粒细胞ⅡA/β-actin比值为(0.35±0.12)较正常对照中性粒细胞ⅡA/β-actin(0.874±0.18)相比明显减少,相当于正常中性粒细胞的39%(均值39%,范围:33%-44%),有统计学意义(P＜0.01)。非肌性肌球蛋白ⅡA、非肌性肌球蛋白ⅡB在HEK-293细胞中均有较高的表达,特异性引物扩增ⅡA的片段大小为331bp,ⅡB的片段大小为492bp。HEK-293细胞裂解液用特异性的非肌性肌球蛋白ⅡA抗体进行免疫共沉淀分析,发现非肌性肌球蛋白ⅡA和非肌性肌球蛋白ⅡB均有表达。阴性对照两者均无表达。
结论:
1.国内首次报道Fechtner综合征家系。
2.国际上首次报道R1933X突变位点同时出现了。肾脏病变,证实过去命名的May-Hegglin异常、Sebastian综合征、Fechmer综合征和Epstein综合征是同一种疾病的不同表现。
3.建立了诊断MYH9综合征的快速简便的免疫荧光方法,较以往的免疫荧光方法相比,更清晰和方便地显示中性粒细胞核和包涵体的结构。
4.国际上首次运用HE染色、免疫组化、免疫荧光和电镜对R1933X基因突变的Fechtner综合征患者的肾脏病变进行了研究,并提出突变的ⅡA间接影响了足细胞SD分子的功能抑或是影响了足细胞细胞骨架导致了肾脏病变的发生。
5国内首次对非肌性肌球蛋白ⅡA的功能进行了初步研究,提出负显性效应导致了中性粒细胞包涵体的产生。ⅡA和ⅡB有明显的相互用,提示ⅡB至少是部分补偿了Fechtner综合征突变的ⅡA蛋白的作用并延缓了组织的功能障碍。
Fechtner syndrome is a rare autosomal dominant disorder characterized by the triad of thrombocytopenia,giant platelet and inclusion bodies in neutrophils and renal lesion, deafness and ocular lesion.It results from mutations in the human MYH9 gene,which encodes nonmuscle myosin-ⅡA heavy chain.Differences in the heavy chains produce three isoforms of classⅡnon-muscle myosins(A,B and C),which are widely distributed in most tissues and cells.They participate in mobility,cytokinesis,phagocytosis, maintenance of cell shape Nearly all forms are expressed in kidney,cochlea and lens. However,megakaryocytic and granulocytic lineage express onlyⅡ-A.Little is known about the pathogenesis of MYH9 syndrome and specific functional role of nonmuscle myosin.
Objective:To identify molecular mechanism underlying Fechtner syndrome in a Chinese family by exploring clinic and genetic defect,the pathogenesis of renal lesion and functional study of non-muscle myosin-ⅡA.
Methods:1.The characteristic morphological features of platelets and leukocytes are examined on blood smears with Wright's-Giemsa staining.Genomic DNA was isolated from peripheral blood of the proband and 9 members of his family.All the exons and exon-intron boundaries of the MYH9 gene were amplified by PCR followed by direct sequencing.2.Ultrastructure of platelet and leukocyte are investigated under electron microscope.3.Indirect immunofluorescence with DAPI staining technology was used to observe the location of nonmuscle myosinⅡA in patients' peripheral blood smear.4.Pathological features of glomerulonephritis were explored by HE staining,immunochemistry,immunofluorescence and electron microscopy of kidney tissues.5.HEK-293 cells are adopted to perform co-immunoprecipitation study.
Results:1.Patients present characteristic clinical features including macrothrombocytopenia, leukocyte inclusions and/or hereditary nephritis.A heterozygous C to T mutation was found in the proband and three members of his family at nucleotide 5981 in exon 40 of MYH9 gene,resulting in a nonsense mutation which encoded truncated protein owing to its premature termination at the Arg 1933 codon.2.Although the platelet is large,the relative numbers of granules,mitochondria and dense bodies is not unusual.Microtubles and elements of the dense tubular system of channels are present.General features of neutrophil morphology are normal.However,a small inclusion is present in the cytoplasm and its area is clear of granules and other organdelles and contains ribosomes.3.There appears abnormal nonmuscle myosinⅡA aggregates in cytoplasm of neutuophils which is similar to the Wright's-Giemsa staining in location and size of inclusions.4.Immunochemistry analysis shows thatⅡA is expressed in the podocyte of glomeruli and distal convoluted ubular,and faintly in the brush berder in proximal tubular.Histological examination observes that glome-rulosclerosis and decreased expression ofⅡA in podocyte.By standard immunofluorescence,the expression ofⅡA in podocyte is higher than normal podocytes and loss of interpodocyte slit diaphragm.5.The calculatedⅡA/β-actin ratio for Fechtner syndrome granulocytes was 39%of control conditions(median:range 33%-44%).The expression ofⅡA andⅡB are identified in HEK-293 cells by RT-PCR.The interaction ofⅡA andⅡB is confirmed by co-immunoprecipation in HEK-293 cells.
Conclusions:
1.We first report a Chinese family with Fechtner syndrome.
2.The patient with R1933X mutaion of MYH9 gene presents inherited glomerulonephritis,which,to our knowledge,has not been reported in the literature.
3.Indirect immunofluorescence with DAPI staining technology is a simple and sensitive method for the diagnosis of MYH9 syndrome.
4.ⅡA has probably an effect on SD molecule or the alteration of podocyte cytoskeleton,which leads to the appearance of glomerulonephritis.
5.As far as granulocytes are concerned,a dominant-negative effect of mutant allele is involved in the formation of inclusion bodies.ⅡB compensate for the isoform A defect derived from MYH9 mutations,and delay or prevent the development of clinically relevant abnormalities.
目的:对1例遗传性Fechtner综合征家系进行临床特征和分子诊断、肾脏病变的机理和非肌性肌球蛋白ⅡA功能等方面的研究。以期初步阐明Fechtner综合征发病的分子机制。
方法:1.外周血片观察血小板和中性粒细胞形态,提取Fechtner综合征家系先证者及其家系成员外周血基因组DNA,PCR法扩增其MYH9基因所有40个外显子和侧翼序列,DNA序列分析确定MYH9基因异常。2.透射电镜观察Fechtner综合征先证者血小板和中性粒细胞的超微结构。3.间接免疫荧光方法结合DAPI复染细胞核的技术观察中性粒细胞包涵体的形态。4.HE染色、免疫组化、免疫荧光和电镜对Fechtner综合征患者的肾脏病变进行了研究。5.半定量Western-Blot检测中性粒细胞非肌性肌球蛋白ⅡA的表达。以人胚肾细胞(HEK-293)为研究对象对ⅡA、ⅡB之间的相互作用进行了探讨。RT-PCR法检测HEK-293细胞中非肌性肌球蛋白ⅡA、ⅡB的表达,并对其进行了免疫共沉淀的研究。
结果:1.外周血片可见巨大血小板,其中中等大(4-7μm)血小板占血小板的53%,巨大血小板(＞7μm)占9%。中性粒细胞胞浆中出现小的、灰蓝色的包涵体。约74%的中性粒细胞可见到中性粒细胞包涵体。PCR产物多次直接测序,均在先证者的MYH9基因外显子40中发现第5981位核苷酸由C→T杂合性突变,使第1933位密码子(CGA,编码Arg)突变为终止密码TGA。2.先证者的血小板体积大,致密颗粒、线粒体等颗粒的数量未见异常。开放管道系统基本正常。中性粒细胞形态大体正常,但胞浆中存在小的包涵体,不同于其它颗粒或细胞器并且周围无膜分隔。放大电镜倍数后发现包涵体内为致密结构,包含一些粗面内质网并且无颗粒。3.正常对照中性粒细胞胞浆中非肌性肌球蛋白ⅡA呈分散均质性分布,无绿色荧光聚集现象。而先证者及家系其他患者中性粒细胞胞浆中均可见明显团块状、半月形的绿色荧光聚集,其大小、位置与瑞氏染色的中性粒细胞包涵体相同。4.患者肾脏标本HE染色发现在12个肾小球中有6个已明显硬化,其余肾小球的部分节段系膜细胞轻.中度增生伴基质增多,并有少数节段与球囊壁粘连。间质炎症细胞小灶性分布,主要围绕在硬化肾小球周围,少数肾小管有蛋白管型。局灶性肾小管上皮细胞肿胀,颗粒变性。肾脏免疫组化观察到非肌性肌球蛋白ⅡA主要位于肾小球脏层上皮细胞(足细胞)和远曲小管上皮,微弱表达于近曲小管刷状缘。与正常肾组织相比,Fechmer综合征患者非肌性肌球蛋白HA在肾小球足细胞的表达减少,非肌性肌球蛋白ⅡA在远曲小管的表达与正常无差别。肾脏免疫荧光提示患者非肌性肌球蛋白ⅡA在肾小球的绿色荧光强度明显高于正常人,通过足细胞特异性抗体染色分析,非肌性肌球蛋白ⅡA主要沉积在肾小球足细胞,并且系膜细胞和系膜基质轻度增生。患者肾脏标本电镜显示2个肾小球,其中1个已发生硬化,另1个为节段性硬化。肾小球系膜区有中度电子致密物沉积,伴有局部系膜细胞增生及基质增多。足突部分融合伴少量微绒毛形成。5.免疫印迹显示先证者中性粒细胞ⅡA/β-actin比值为(0.35±0.12)较正常对照中性粒细胞ⅡA/β-actin(0.874±0.18)相比明显减少,相当于正常中性粒细胞的39%(均值39%,范围:33%-44%),有统计学意义(P＜0.01)。非肌性肌球蛋白ⅡA、非肌性肌球蛋白ⅡB在HEK-293细胞中均有较高的表达,特异性引物扩增ⅡA的片段大小为331bp,ⅡB的片段大小为492bp。HEK-293细胞裂解液用特异性的非肌性肌球蛋白ⅡA抗体进行免疫共沉淀分析,发现非肌性肌球蛋白ⅡA和非肌性肌球蛋白ⅡB均有表达。阴性对照两者均无表达。
结论:
1.国内首次报道Fechtner综合征家系。
2.国际上首次报道R1933X突变位点同时出现了。肾脏病变,证实过去命名的May-Hegglin异常、Sebastian综合征、Fechmer综合征和Epstein综合征是同一种疾病的不同表现。
3.建立了诊断MYH9综合征的快速简便的免疫荧光方法,较以往的免疫荧光方法相比,更清晰和方便地显示中性粒细胞核和包涵体的结构。
4.国际上首次运用HE染色、免疫组化、免疫荧光和电镜对R1933X基因突变的Fechtner综合征患者的肾脏病变进行了研究,并提出突变的ⅡA间接影响了足细胞SD分子的功能抑或是影响了足细胞细胞骨架导致了肾脏病变的发生。
5国内首次对非肌性肌球蛋白ⅡA的功能进行了初步研究,提出负显性效应导致了中性粒细胞包涵体的产生。ⅡA和ⅡB有明显的相互用,提示ⅡB至少是部分补偿了Fechtner综合征突变的ⅡA蛋白的作用并延缓了组织的功能障碍。
Fechtner syndrome is a rare autosomal dominant disorder characterized by the triad of thrombocytopenia,giant platelet and inclusion bodies in neutrophils and renal lesion, deafness and ocular lesion.It results from mutations in the human MYH9 gene,which encodes nonmuscle myosin-ⅡA heavy chain.Differences in the heavy chains produce three isoforms of classⅡnon-muscle myosins(A,B and C),which are widely distributed in most tissues and cells.They participate in mobility,cytokinesis,phagocytosis, maintenance of cell shape Nearly all forms are expressed in kidney,cochlea and lens. However,megakaryocytic and granulocytic lineage express onlyⅡ-A.Little is known about the pathogenesis of MYH9 syndrome and specific functional role of nonmuscle myosin.
Objective:To identify molecular mechanism underlying Fechtner syndrome in a Chinese family by exploring clinic and genetic defect,the pathogenesis of renal lesion and functional study of non-muscle myosin-ⅡA.
Methods:1.The characteristic morphological features of platelets and leukocytes are examined on blood smears with Wright's-Giemsa staining.Genomic DNA was isolated from peripheral blood of the proband and 9 members of his family.All the exons and exon-intron boundaries of the MYH9 gene were amplified by PCR followed by direct sequencing.2.Ultrastructure of platelet and leukocyte are investigated under electron microscope.3.Indirect immunofluorescence with DAPI staining technology was used to observe the location of nonmuscle myosinⅡA in patients' peripheral blood smear.4.Pathological features of glomerulonephritis were explored by HE staining,immunochemistry,immunofluorescence and electron microscopy of kidney tissues.5.HEK-293 cells are adopted to perform co-immunoprecipitation study.
Results:1.Patients present characteristic clinical features including macrothrombocytopenia, leukocyte inclusions and/or hereditary nephritis.A heterozygous C to T mutation was found in the proband and three members of his family at nucleotide 5981 in exon 40 of MYH9 gene,resulting in a nonsense mutation which encoded truncated protein owing to its premature termination at the Arg 1933 codon.2.Although the platelet is large,the relative numbers of granules,mitochondria and dense bodies is not unusual.Microtubles and elements of the dense tubular system of channels are present.General features of neutrophil morphology are normal.However,a small inclusion is present in the cytoplasm and its area is clear of granules and other organdelles and contains ribosomes.3.There appears abnormal nonmuscle myosinⅡA aggregates in cytoplasm of neutuophils which is similar to the Wright's-Giemsa staining in location and size of inclusions.4.Immunochemistry analysis shows thatⅡA is expressed in the podocyte of glomeruli and distal convoluted ubular,and faintly in the brush berder in proximal tubular.Histological examination observes that glome-rulosclerosis and decreased expression ofⅡA in podocyte.By standard immunofluorescence,the expression ofⅡA in podocyte is higher than normal podocytes and loss of interpodocyte slit diaphragm.5.The calculatedⅡA/β-actin ratio for Fechtner syndrome granulocytes was 39%of control conditions(median:range 33%-44%).The expression ofⅡA andⅡB are identified in HEK-293 cells by RT-PCR.The interaction ofⅡA andⅡB is confirmed by co-immunoprecipation in HEK-293 cells.
Conclusions:
1.We first report a Chinese family with Fechtner syndrome.
2.The patient with R1933X mutaion of MYH9 gene presents inherited glomerulonephritis,which,to our knowledge,has not been reported in the literature.
3.Indirect immunofluorescence with DAPI staining technology is a simple and sensitive method for the diagnosis of MYH9 syndrome.
4.ⅡA has probably an effect on SD molecule or the alteration of podocyte cytoskeleton,which leads to the appearance of glomerulonephritis.
5.As far as granulocytes are concerned,a dominant-negative effect of mutant allele is involved in the formation of inclusion bodies.ⅡB compensate for the isoform A defect derived from MYH9 mutations,and delay or prevent the development of clinically relevant abnormalities.
引文
1. Seri M,Cusano R,Gangarossa S,et al.Mutations in MYH9 result in the May-Hegglin anomaly,and Fechtner and Sebastain syndromes. The May-Hegglin/Fechtner Syndome Consortium.Nat Gene.2000;26:103-105
2. Seri M,Savino M,Bordo D,et al.Eptein syndome:another renal disorder with mutations in the nonmuscle myosin heavy chain 9 gene.Hum Gene. 2002; 110:182-186.
3. Kelley MJ,Jawien W,Ortel TL,et al.Mutation of MYH9,encoding non-muscle myosin heavy chain A,in May-Hegglin anomaly.Nat Genet.2000;26:106-108.
4. Kunishima S,Kojima T,matsushita Y,et al.Mutations in the NMMHC-A gene cause autosomal dominant macrothrombocytopenia with leukocyte(May-Hegglin anomaly/ Sebstain syndrome).Blood.2001;97:1147-1149.
5. Kunishima S,Matsushita t,Kojima T,et al.Identification of six novel MYH9 mutaions and genotype-phenotype relationships in autosomal dominant macros- thrombocytopenia with leukocyte inclusions.J Hum Genet.2001;46:722-729
6. Seri M,Pecci A,Di Bari F,et al.MYH9-related disease:May-Hegglin anomaly,Sebstain syndome,Fechtner syndrome, and Epstetin sydrome are not distinct entities but represent a variable expression of a single illness. Medicine. 2003;82:203-215
7. Heath KE,Campos-Barros A,Toren A,et al.Non-muscle myosin heavy chain IIA mutaions define a spectrum of autosomal dominant macrothrombocytopenia:May-Hegglin anomaly and Fechtner syndrome,Sebstain,Epstein, and Alport-like syndromes.Am J Hum Gene.2001;12:780-794.
8. Dong F, Li S, Pujol-Moix N, et al.Genotype-phenotype correlation in MYH9-related thrombocytopenia. Br J Haematol. 2005,130:620-627.
9. Frank J,Dong F,Rickoll W,et al.Rod mutations associated with MYH9-related disorders disrupt nonmuscle myosin-IIA assembly.Blood.2005;105:161-169
10. Robinson DN,Spudich JA. Toward a molecular understanding of cytokinesis.Trends Cell Biol,2000:228-237.
11. Wei Q,Adelstein RS.Conditional expression of a truncated fragment of nonmuscle myosin II-A alters cell shape but not cytokinesis in Hela cells.Mol Biol Cell.2000:3617-3627
12. Jacobelli J,Chmura S.A.,Buxton DB,et al.A single class II myosin modulates T cell motility and stopping,but not synapse formation. Nature Immunol,2004:531-538.
13. Simons M,Wang M,McBride OW,et al. Human nonmuscle myosin heavy chains are encoded by two genes located on different chromosomes, Circ. Res., 1991;69:530-539
14. Leal A,Endele S,Huehne K,et al.A novel myosin heavy chain gene in human chromosome 19q13.3,Gene,2003;312:165-171.
15. Buxton DB.,Golomb E,Adelstein R.S., Induction of nonmuscle myosin heavy chain II-C by butyrate in RAW 264.7 mouse macrophages.,J. Biol., Chem, 2003,278:15449-15455.
16. Marigo V,Nigro A,Pecci A,et al.Correlation between the clinical phenotype of MYH9-related disease and tissue distribution of class II nonmuscle myosin heavy chains.Genomics.2004;83:1125-1133.
1.Peterson LC,Rao KV,Crosson JT,et al.Fechtner syndrome--a variant of Alport's syndrome with leukocyte inclusions and macrothrombocytopenia.Blood,1985,65:397-406.
2.Toren A,Rozenfeld-Granot G,Rocca B,et al.Autosomal-dominant giant platelet syndromes:a hint of the same genetic defect as in Fechtner syndrome owing to a similar genetic linkage to chromosome 22q11-13.Blood,2000,96:3447-3451.
3.May-Hegglin/Fechtner Syndrome Consortium:Mutations in MYH9 result in the May-Hegglin anomaly,and Fechtner and Sebastian syndromes.Nature Gene,2000,26:103-105
4.Seri M,Savino M,Bordo D,et al.The Epstein syndrome:A further renal disorder due to mutations in the non-muscle myosin heavy chain 9 gene.Hum Genet.2002,110:182-186.
5.张广森,易彦,徐敏,等.一个May-Hegglin异常家系非肌性肌球蛋白重链9基因突变位点的鉴定.中华医学杂志,2002,82:918-920.
6.邵秀如,李家增,马军,等.一例May-Hegglin异常家系临床及分子生物学研究.中华血液学杂志,2004,25:548-551.
7.Greinacher A,Mueller-Eckhardt C.Hereditary types of thrombocytopenia with giant platelets and inclusion bodies in the leukocytes.Blut,1990,60:53-60.
8.Epstein CJ,Sahud MA,Piel CF,et al.Hereditary macrothrombocytopathia,nephritis and deafness.Am J Med,1972,52:299-310
9.Yoshinari M,Kunishima S,Miyabayashi S,et al.A Unique Immunofluorescence Method Promotes Accurate Diagnosis in MYH9 Disorders:A Case Report.J Pediatr Hematol Oncol,2004,26(9):579-583.
10.Heath KE,Campos-Barros A,TorenA.Nonmuscle myosin heavy chain ⅡA mutation define a spectrum of autosomal dominant macrothrombocytopenias:May-Hegglin anomaly and Fechtner,Sebastian,Epstein,and Alport-like syndromes.Am J Hum Genet,2001,69:1033-1045.
11.Sellers JR.Myosins:a diverse superfamily.Biochim Biophys Acta,2000,1496,3-22.
12.Balduini CL,Savoia A.Inherited thrombocytopenia:molecular mechanisms.Semin Thromb Hemost,2004,30:513-523.
13.Balduini CL,Iolascon A,Savoia A.Inherited thrombocytopenias:from genes to therapy.Hamatologica,2002,87:860-880.
14.Pecci A,Canbbio I,Balduini A,et al.Pathogenetic mechanisms of hematological abnormalities of patients with MYH9 mutations.Hum Mol Genet,2005,14:3169-3178
15. Hu A,Wang F,Sellers JR,et al. Mutations in human nonmuscle myosin IIA found in patients with May-Hegglin anomaly and Fechtner syndrome result in impaired enzymatic function. J Biol Chem, 2002 ,277:46512-46517.
16. Kunishima S, Matsushita T, Kojima T,et al.Immunofluorescence analysis of neutrophil nonmuscle myosin heavy chain A in MYH9 disorders :association of subcellular localization with MYH9 mutation. Lab Invest, 2003,83:115-122.
17. Ghiggeri GM, Caridi G, Magrini U.,et al.Genetics,clinical and pathological features of glomerulonephrites associated with mutations of nonmuscle myosin IIA(Fechtner syndrome). Am J Kidney Dis,2003, 41:95-104.
18. Dong F, Li S, Pujol-Moix N, et al.Genotype-phenotype correlation in MYH9-related thrombocytopenia. Br J Haematol. 2005,130:620-627.
19. Kunishima S, Matsushita T, Kojima T, et al. Identification of six novel MYH9 mutations and genotype-phenotype relationships in autosomal dominant macrothrombocytopenia with leukocyte inclusions. J Hum Genet. 2001,46:722-729.
20. Basile C, Schiavone P, Heidet L,et al.Hereditary nephritis with macrothrombocytopenia: phenotypic variety and the genotypic defect. J Nephrol, 2002 ,15:320-323.
1.Peterson LC,Rao KV,Crosson JT,et al.Fechtner syndrome--a variant of Alport's syndrome with leukocyte inclusions and macrothrombocytopenia.Blood,1985,65:397-406.
2.May-Hegglin/Fechtner Syndrome Consortium:Mutations in MYH9 result in the May-Hegglin anomaly,and Fechtner and Sebastian syndromes.Nature Gene,2000,26:103-105
3.Seri M,Savino M,Bordo D,et al.The Epstein syndrome:A further renal disorder due to mutations in the non-muscle myosin heavy chain 9 gene.Hum Genet.2002,110:182-186.
4.Toren A,Rozenfeld-Granot G;Rocca B,et al.Autosomal-dominant giant platelet syndromes:a hint of the same genetic defect as in Fechtner syndrome owing to a similar genetic linkage to chromosome 22q11-13.Blood,2000,96:3447-3451.
5.Kunishima S,Matsushita T,Kojima T,et al.Identification of six novel MYH9mutations and genotype-phenotype relationships in autosomal dominant mactothrombocytopenia with leukocyte inclusions.J Hum Gene.2001,46:722-729
6.杨海燕 王兆钺 苏雁华等Fechtner综合征临床与分子缺陷研究伴文献复习.中华血液学杂志 2007,28(3):160-164.
7.Kunishima S,Matsushita Y,Kojima T,et al.Immunofluorescence analysis of neutrophil nonmuscle myosin heavy chain-A in MYH9 disorders:association of subcellular localization with MYH9 mutations.Lab Invest.2003;83:115-122.
8.Pecci A,Noris P,Invernizzi R,et al.Immunocytochemistry for the heavy chain of the non-muscel myosin ⅡA as a diagnostic tool for MYH9-related disorders.Br J Haematol.2002,25:164-167.
9. Itoh H,Ueguchi-Tanaka M,Sato Y,et al.The Gibberellin Signaling Pathway Is Regulated by the Appearance and Disoppearance of SLENDER RICE1 in Nuclei.The Plant Cell,2002:57-60
10. Basile C, Schiavone P, Heidet L,et al.Hereditary nephritis with macrothrombocytopenia: phenotypic variety and the genotypic defect. J Nephrol, 2002 ,15:320-323.
1.Moxey-Mims MM,Young G,Silverman A,et al.End stage renal disease in two pediatric patients with Fechtner syndrome.Pediatr Nephrol,1999,13:782-786.
2.Berg JS,Powell BC,Cheney RE,A millennial myosin census,Mol.Biol.Cell,2001,12:780-794
3.Marigo V,Nigro A,Pecci A,et al.Correlation between the clinical phenotype of MYH9-related disease and tissue distribution of class Ⅱ nonmuscle myosin heavy chains.Genomics.,2004,83:1125-1133.
4.Arrondel C,Vodovar N,Knebelmann B,et al.Expression of the nonmuscle myosin heavy chain IIA in the human kidney and screening for MYH9 mutations in Epstein and Fechtner syndromes ,J Am Soc Nephrol, 2002 ,13:65-74.
5. Simons M,Wang M,Mcbride OW,et al.,Human nonmuscle myosin heavy chains are encoded by two genes located on different chromosomes,Circ. Res. 1991,69:530-539.
6. Leal A,Endele S,Stengel C,et al.A novel myosin heavy chain gene in human chromosome19q13.3.Gene,2003,312:165-171.
7. 7 Dong F, Li S, Pujol-Moix N, et al.Genotype-phenotype correlation in MYH9 -relatedthrombocytopenia. Br J Haematol. 2005,130:620-627.
8. Kunishima S, Matsushita T, Kojima T, et al. Identification of six novel MYH9 mutations and genotype-phenotype relationships in autosomal dominant macrothrombocytopenia with leukocyte inclusions. J Hum Genet. 2001,46:722-729.
9. Ghiggeri GM,Caridi G,Magrini U,et al. Genetics, clinical and pathological features of glomerulonephritis associated with mutations of nonmuscle myosin IIA (Fechtner syndrome).Am J Kidney Dis,2003,41:95-104
10. Arrondel C,Vodovar N,Knebelmann B,et al.Expression of the nonmuscle myosin heavy chain IIA in the human kidney and screening for MYH9 mutations in Epstein and Fechtner Syndrome.J Am Soc Nephrol,2001,13:65-74.
11. Huber TB,Michael K,Gerd W,et al.Interaction with podocin facilitates nephrin sigaling.J Biochemistry,2001,276:41543-41546
12. Kawachi H,Koike H,Kurihara H,et al.Cloing of rat homologre of podocin: expression in proteinuria states and in developing glomeruli. J Am Soc Nephrol,2003,14,46-56
13. Kaplam JM,Kim SH,North KN,et al.Mutation in ACTN4 encoding a -actinin-4,cause familial focal segmental glomerulosclerosis.Nature Genet, 2000,24:251-256
14. Tryggvason K.Unraveling the mechanisms of glomerular ultrafitration:nephrin,a key component of the split diaphragm. J Am Soc Nephrol,1999,10:2440-2445.
15. Kritz W.Podocyte is the major culprit accounts for the progression of chronic renal disease.Microsc Res Tech,2002,57,189-195
16. Mundel P,Shankland SJ.Podocyte biology and response to injury. J Am Soc Nephrol,2002,13:3005-3015
17. Vaughan MR,Pippin JW,Griffin SV,et al.ATRA induces podocytedifferentiation and alters nephrin and podocin expression in vitro and in vivo.Kidney Int, 2005,68:133-144
18. Shibata S,Nagase M,Fujita T.Fluvastatin ameliorates podocyte injury in proteinuric rats via modulation of excessive Rho signaling.J Am Soc Nephrol, 2006, 17:754-764.
1.Sellers JR.Myosins:a diverse superfamily.Biochim Biophys Acta,2000:3-22.
2.Robinson DN,Spudich JA.Toward a molecular understanding of cytokinesis.Trends Cell Biol,2000:228-237.
3.Wei Q,Adelstein RS.Conditional expression of a truncated fragment of nonmuscle myosin Ⅱ-A alters cell shape but not cytokinesis in Hela cells.Mol Biol Cell.2000:3617-3627
4. Jacobelli J,Chmura S.A.,Buxton DB,et al.A single class II myosin modulates T cell motility and stopping,but not synapse formation. Nature Immunol,2004:531-538.
5. Simons M,Wang M,McBride OW,et al. Human nonmuscle myosin heavy chains are encoded by two genes located on different chromosomes, Circ. Res., 1991:530-539
6. Leal A ,Endele S,Huehne K,et al.A novel myosin heavy chain gene in human chromosome 19q13.3,Gene,2003:165-171.
7. Buxton DB.,Golomb E,Adelstein R.S., Induction of nonmuscle myosin heavy chain II-C by butyrate in RAW 264.7 mouse macrophages.,J. Biol.Chem,2003:15449-15455.
8. Maupin P,Philips CL,Adelstein RS,et al.Differential localization of myosin-H isozymes in human cultured cells and blood cells.J Cell Sci,1994,107:3077-3090.
9. Mansfield PJ,Shayman JA,Boxter LA.Regulation of polymophonuclear leukocyte phagocytosis by myosin light chain kinase after activation of mitogen-activated protein kinase.Blood,2000:2407-2412
10. Deutsch S, Rideau A,Merla G,et al.Aspl424Asn MYH9 mutation results in a unstable protein responsible for the phenotypes in May-Hegglin anomaly/Fechtner syndrome.Blood,2003:529-534.
11. Pecci A,Canobbio I,Balduini A,et al.Pathogenetic mechanisms of hematological abnormalities of patients with MYH9 mutations.Human Molecular Genetics,2005:3169-3178.
12. Yi Y,Zhang GZ,Mu M,et al.Analysis of clinical manifestations,mutant gene and encoded protein in two Chinese MYH9-related disease families.Clinica Chimica Acta,2006:49-54.
13. Franke JD,Dong F,Rickoll WL,et al.Rod mutations associated with MYH9-related disorders disrupt non-muscle myosin-IIA assembly.Blood,2005:161-1
14. Conti MA,Even -Ram S,Liu C,et al. Defects in cell adhesion and the visceral endoderm following ablation of nonmuscle myosin heavy chain II-A in mice.J Biol Chem. 2004:41263-41266.
15. Tullio AN,Accili D,Ferrans VJ, Yu ZX,et al.Nonmuscle myosin II-B is required for normal development of the mouse heart.Proc Natl Acad Sci USA,1997:12407-12412.
16. Kovacs M,Wang F,Hu A,et ai.Functional divergence of human cytoplasmic myosin II:kinetic characterization of the non-muscle HA isoform.J Biol Chem,2003:38132-38140.
17. Wang Q,Moncman CL,Winkelmann DA.Mutations in the motor domain modulate myosin activity and myofribri organization.J Cell Sci,2003:4227-4238
18. Marini Monica,Bruschi M,Pecci A,et al.Non-muscle myosin heavy chain IIA and IIB interact and co-localize in living cells:Relevance for MYH9-related disease.Int J Mol Med,2006:729-736.
19. Mango Valeria,Nigro A,Pecci A,et al.Correlation between the clinical phenotype of MYH9-related disease and tissue distribution of classs II nonmuscle myosin heavy chains,2004:1125-1133.
1.Mhawech P,Saleem A.Inherited giant platelet disorders:classification and literature review.Am J Clin Pathol,2000,1139(2):176-190.
2.Wang ZY,Zhao XJ,Duan WM,et al.A novel mutation in the transmembrane region of glycoprotein Ⅸ associated with Bernard-Soulier syndrome.Thromb Haemost,2004,92(3):606-613.
3 Hartwig J,Italiano J Jr.The birth of the platelet.J Thromb Haemost,2003,1(7):1580-1586.
4 Seri M,Pecci A,Di Bari F,et al.MYH9—related disease:May-Hegglin anomaly,Sebastian syndrome,Fechtner syndrome,and Epstein syndrome are not distinct entities but represent a variable expression of a single illness.Medicine,2003,82(3):203-215.
5 Heath KE,Campos-Barros A,TorenA.Nonmuscle myosin heavy chain ⅡA mutation define a spectrum of autosomal dominant macrothrombocytopenias:May-Hegglin anomaly and Fechtner,Sebastian,Epstein,and Alport-like syndromes.Am J Hum Genet,2001,69(5):1033-1045.
6 Hu A,Wang F,Sellers JR.Mutation in human nonmuscle myosin ⅡA found in patients with May-Hegglin anomaly and Fechtner syndrome result in impaired enzymatic function.J Biol Chem,2002,277(48):46512-46517.
7 Deutseh S,Rideau A,Bochaton-Piallat M,et al.Asp1424Asn MYH9 mutation results in unstable protein responsible for the phenotypes in May-Hegglin anomaly/Fechtner syndrome.Blood,2003,102(2):529-534.
8 张广森,易彦,徐敏,等.一个May-Hegglin异常家系非肌性肌球蛋白重链9基因突变位点的鉴定.中华医学杂志,2002,82(13):918-920.
9 Pestina TI,Jackson CW,Stenberg PE.Abnormal subcellular distribution of myosin and talin in Wistar Furth rat platelet.Blood,1995,85(9):2346-2446.
10 Drouin A,Favier R,Masse JM,et al.Newly recognized cellular abnormalities in the gray platelet syndrome.Blood,2001,98(5):1382-1391.
11 White JG.Giant electron-dense chains,clusters and granules in megakaryocytes and platelets with normal dense bodies:an inherited thrombocytopenic disorder I.Megakaryocytes.Platelets,2003,14(1):53-60.
12 White JG,Gilbert G,Ahlstrand.Giant electron dense chains,clusters and granules in megakaryocytes and platelets with normal dense bodies:an inherited thrombocytopenic disorder Ⅳ.Ultrastructural cytochemistry and analytical electron microscopy.Platelets,2003,14(5):313-324.
13 Okita JR, Frojmovic MM, Kristopeit S, et al. Montreal platelet syndrome:a defect in calcium-activated neutral Proteinase(calpain). Blood, 1989,74(2):715-721.
14 Wang ZY, Shi J, Han Y, et al. Spontaneous platelet aggregation with congenital giant platelet containing large granules and thick membrane. Clin Appl Thromb Hemost, 2001,7(4):305-310.
15 Yoshinari M, Kunishima S, Miyabayashi S, et al. A Unique Immunofluorescence Method Promotes Accurate Diagnosis in MYH9 Disorders:A Case Report. J Pediatr Hematol Oncol, 2004,26(9):579-583.
2. Seri M,Savino M,Bordo D,et al.Eptein syndome:another renal disorder with mutations in the nonmuscle myosin heavy chain 9 gene.Hum Gene. 2002; 110:182-186.
3. Kelley MJ,Jawien W,Ortel TL,et al.Mutation of MYH9,encoding non-muscle myosin heavy chain A,in May-Hegglin anomaly.Nat Genet.2000;26:106-108.
4. Kunishima S,Kojima T,matsushita Y,et al.Mutations in the NMMHC-A gene cause autosomal dominant macrothrombocytopenia with leukocyte(May-Hegglin anomaly/ Sebstain syndrome).Blood.2001;97:1147-1149.
5. Kunishima S,Matsushita t,Kojima T,et al.Identification of six novel MYH9 mutaions and genotype-phenotype relationships in autosomal dominant macros- thrombocytopenia with leukocyte inclusions.J Hum Genet.2001;46:722-729
6. Seri M,Pecci A,Di Bari F,et al.MYH9-related disease:May-Hegglin anomaly,Sebstain syndome,Fechtner syndrome, and Epstetin sydrome are not distinct entities but represent a variable expression of a single illness. Medicine. 2003;82:203-215
7. Heath KE,Campos-Barros A,Toren A,et al.Non-muscle myosin heavy chain IIA mutaions define a spectrum of autosomal dominant macrothrombocytopenia:May-Hegglin anomaly and Fechtner syndrome,Sebstain,Epstein, and Alport-like syndromes.Am J Hum Gene.2001;12:780-794.
8. Dong F, Li S, Pujol-Moix N, et al.Genotype-phenotype correlation in MYH9-related thrombocytopenia. Br J Haematol. 2005,130:620-627.
9. Frank J,Dong F,Rickoll W,et al.Rod mutations associated with MYH9-related disorders disrupt nonmuscle myosin-IIA assembly.Blood.2005;105:161-169
10. Robinson DN,Spudich JA. Toward a molecular understanding of cytokinesis.Trends Cell Biol,2000:228-237.
11. Wei Q,Adelstein RS.Conditional expression of a truncated fragment of nonmuscle myosin II-A alters cell shape but not cytokinesis in Hela cells.Mol Biol Cell.2000:3617-3627
12. Jacobelli J,Chmura S.A.,Buxton DB,et al.A single class II myosin modulates T cell motility and stopping,but not synapse formation. Nature Immunol,2004:531-538.
13. Simons M,Wang M,McBride OW,et al. Human nonmuscle myosin heavy chains are encoded by two genes located on different chromosomes, Circ. Res., 1991;69:530-539
14. Leal A,Endele S,Huehne K,et al.A novel myosin heavy chain gene in human chromosome 19q13.3,Gene,2003;312:165-171.
15. Buxton DB.,Golomb E,Adelstein R.S., Induction of nonmuscle myosin heavy chain II-C by butyrate in RAW 264.7 mouse macrophages.,J. Biol., Chem, 2003,278:15449-15455.
16. Marigo V,Nigro A,Pecci A,et al.Correlation between the clinical phenotype of MYH9-related disease and tissue distribution of class II nonmuscle myosin heavy chains.Genomics.2004;83:1125-1133.
1.Peterson LC,Rao KV,Crosson JT,et al.Fechtner syndrome--a variant of Alport's syndrome with leukocyte inclusions and macrothrombocytopenia.Blood,1985,65:397-406.
2.Toren A,Rozenfeld-Granot G,Rocca B,et al.Autosomal-dominant giant platelet syndromes:a hint of the same genetic defect as in Fechtner syndrome owing to a similar genetic linkage to chromosome 22q11-13.Blood,2000,96:3447-3451.
3.May-Hegglin/Fechtner Syndrome Consortium:Mutations in MYH9 result in the May-Hegglin anomaly,and Fechtner and Sebastian syndromes.Nature Gene,2000,26:103-105
4.Seri M,Savino M,Bordo D,et al.The Epstein syndrome:A further renal disorder due to mutations in the non-muscle myosin heavy chain 9 gene.Hum Genet.2002,110:182-186.
5.张广森,易彦,徐敏,等.一个May-Hegglin异常家系非肌性肌球蛋白重链9基因突变位点的鉴定.中华医学杂志,2002,82:918-920.
6.邵秀如,李家增,马军,等.一例May-Hegglin异常家系临床及分子生物学研究.中华血液学杂志,2004,25:548-551.
7.Greinacher A,Mueller-Eckhardt C.Hereditary types of thrombocytopenia with giant platelets and inclusion bodies in the leukocytes.Blut,1990,60:53-60.
8.Epstein CJ,Sahud MA,Piel CF,et al.Hereditary macrothrombocytopathia,nephritis and deafness.Am J Med,1972,52:299-310
9.Yoshinari M,Kunishima S,Miyabayashi S,et al.A Unique Immunofluorescence Method Promotes Accurate Diagnosis in MYH9 Disorders:A Case Report.J Pediatr Hematol Oncol,2004,26(9):579-583.
10.Heath KE,Campos-Barros A,TorenA.Nonmuscle myosin heavy chain ⅡA mutation define a spectrum of autosomal dominant macrothrombocytopenias:May-Hegglin anomaly and Fechtner,Sebastian,Epstein,and Alport-like syndromes.Am J Hum Genet,2001,69:1033-1045.
11.Sellers JR.Myosins:a diverse superfamily.Biochim Biophys Acta,2000,1496,3-22.
12.Balduini CL,Savoia A.Inherited thrombocytopenia:molecular mechanisms.Semin Thromb Hemost,2004,30:513-523.
13.Balduini CL,Iolascon A,Savoia A.Inherited thrombocytopenias:from genes to therapy.Hamatologica,2002,87:860-880.
14.Pecci A,Canbbio I,Balduini A,et al.Pathogenetic mechanisms of hematological abnormalities of patients with MYH9 mutations.Hum Mol Genet,2005,14:3169-3178
15. Hu A,Wang F,Sellers JR,et al. Mutations in human nonmuscle myosin IIA found in patients with May-Hegglin anomaly and Fechtner syndrome result in impaired enzymatic function. J Biol Chem, 2002 ,277:46512-46517.
16. Kunishima S, Matsushita T, Kojima T,et al.Immunofluorescence analysis of neutrophil nonmuscle myosin heavy chain A in MYH9 disorders :association of subcellular localization with MYH9 mutation. Lab Invest, 2003,83:115-122.
17. Ghiggeri GM, Caridi G, Magrini U.,et al.Genetics,clinical and pathological features of glomerulonephrites associated with mutations of nonmuscle myosin IIA(Fechtner syndrome). Am J Kidney Dis,2003, 41:95-104.
18. Dong F, Li S, Pujol-Moix N, et al.Genotype-phenotype correlation in MYH9-related thrombocytopenia. Br J Haematol. 2005,130:620-627.
19. Kunishima S, Matsushita T, Kojima T, et al. Identification of six novel MYH9 mutations and genotype-phenotype relationships in autosomal dominant macrothrombocytopenia with leukocyte inclusions. J Hum Genet. 2001,46:722-729.
20. Basile C, Schiavone P, Heidet L,et al.Hereditary nephritis with macrothrombocytopenia: phenotypic variety and the genotypic defect. J Nephrol, 2002 ,15:320-323.
1.Peterson LC,Rao KV,Crosson JT,et al.Fechtner syndrome--a variant of Alport's syndrome with leukocyte inclusions and macrothrombocytopenia.Blood,1985,65:397-406.
2.May-Hegglin/Fechtner Syndrome Consortium:Mutations in MYH9 result in the May-Hegglin anomaly,and Fechtner and Sebastian syndromes.Nature Gene,2000,26:103-105
3.Seri M,Savino M,Bordo D,et al.The Epstein syndrome:A further renal disorder due to mutations in the non-muscle myosin heavy chain 9 gene.Hum Genet.2002,110:182-186.
4.Toren A,Rozenfeld-Granot G;Rocca B,et al.Autosomal-dominant giant platelet syndromes:a hint of the same genetic defect as in Fechtner syndrome owing to a similar genetic linkage to chromosome 22q11-13.Blood,2000,96:3447-3451.
5.Kunishima S,Matsushita T,Kojima T,et al.Identification of six novel MYH9mutations and genotype-phenotype relationships in autosomal dominant mactothrombocytopenia with leukocyte inclusions.J Hum Gene.2001,46:722-729
6.杨海燕 王兆钺 苏雁华等Fechtner综合征临床与分子缺陷研究伴文献复习.中华血液学杂志 2007,28(3):160-164.
7.Kunishima S,Matsushita Y,Kojima T,et al.Immunofluorescence analysis of neutrophil nonmuscle myosin heavy chain-A in MYH9 disorders:association of subcellular localization with MYH9 mutations.Lab Invest.2003;83:115-122.
8.Pecci A,Noris P,Invernizzi R,et al.Immunocytochemistry for the heavy chain of the non-muscel myosin ⅡA as a diagnostic tool for MYH9-related disorders.Br J Haematol.2002,25:164-167.
9. Itoh H,Ueguchi-Tanaka M,Sato Y,et al.The Gibberellin Signaling Pathway Is Regulated by the Appearance and Disoppearance of SLENDER RICE1 in Nuclei.The Plant Cell,2002:57-60
10. Basile C, Schiavone P, Heidet L,et al.Hereditary nephritis with macrothrombocytopenia: phenotypic variety and the genotypic defect. J Nephrol, 2002 ,15:320-323.
1.Moxey-Mims MM,Young G,Silverman A,et al.End stage renal disease in two pediatric patients with Fechtner syndrome.Pediatr Nephrol,1999,13:782-786.
2.Berg JS,Powell BC,Cheney RE,A millennial myosin census,Mol.Biol.Cell,2001,12:780-794
3.Marigo V,Nigro A,Pecci A,et al.Correlation between the clinical phenotype of MYH9-related disease and tissue distribution of class Ⅱ nonmuscle myosin heavy chains.Genomics.,2004,83:1125-1133.
4.Arrondel C,Vodovar N,Knebelmann B,et al.Expression of the nonmuscle myosin heavy chain IIA in the human kidney and screening for MYH9 mutations in Epstein and Fechtner syndromes ,J Am Soc Nephrol, 2002 ,13:65-74.
5. Simons M,Wang M,Mcbride OW,et al.,Human nonmuscle myosin heavy chains are encoded by two genes located on different chromosomes,Circ. Res. 1991,69:530-539.
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