遗传性痉挛性截瘫致病基因定位及其REEP1和ZFYVE27基因功能的初步研究
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摘要
第一部分:遗传性痉挛性截瘫家系的基因定位与突变分析
研究背景:
遗传性痉挛性截瘫(Hereditary Spastic Paraplegias,HSP)是一组上运动神经变性疾病,其特点是下肢渐进性的痉挛,是由皮质脊髓束运动轴突变性和发育异常引起的。按临床表现可分为单纯型和复杂型,单纯型只表现为进行性双下肢肌张力增高和无力,合并脊髓外损害,如肌肉萎缩、精神发育迟滞、共济失调、多发性神经病、视神经萎缩、视网膜色素变性、耳聋、锥体外系等症状的称为复杂型。按遗传方式分为常染色体显性遗传(ADHSP)、常染色体隐性遗传(ARHSP)X连锁隐性遗传(XRHSP)。遗传性痉挛性截瘫具有很强的异质性,到目前为止,虽然已发现33个HSP疾病基因相关位点,但是只有其中15个疾病基因已被克隆。
研究目的:
研究来自山东5个ADHSP和ARHSP家系,进行致病基因定位和突变筛查,并且分析各型HSP家系基因型和表型的关系,
研究方法:
利用等位基因共享分析、全基因组扫描、连锁分析、定位候选克隆策略,进行致病基因定位与突变筛选。对家系1全部6个患者,家系2的2个患者,进行临床表型分析,电生理和脊髓与大脑的MR的扫描。
研究结果:
1.在家系1中,连锁分析显示微卫星分子标记D15S817和D15S541与致病基因成立连锁关系,定位于SPG6(NIPA1基因)。突变筛查发现NIPA1基因第3外显子第316位碱基野生型G突变成C(G→C),造成106号密码子由Gly→Arg。神经电生理检查显示了大多数患者运动神经的胫神经和腓总神经的混合肌肉动作电位(CMAP)波幅下降。胫神经感觉神经动作电位(SNAP)大多数没有引出。所有患者MEP显示了胫前肌(AT)和第一趾骨间肌(FMI)的中枢运动传导时间(CMCT)或者没有引出,或者明显延长。脊髓MRI显示了脊髓呈不同程度萎缩,相应脊髓节段灰白质分界显示清楚,横轴位T2WI上灰质呈边界清楚、左右对称的点状或点片状高信号,矢状位上表现为连续纵行的条状高信号。灰白质均受累,蛛网膜下腔扩大。
2.在家系2中,连锁分析显示微卫星分子标记D2S2951与D2S2333与致病基因成立连锁关系,定位于SPG31(REEP1基因)。突变筛查发现REEP1基因第5外显子受体位第417+1位碱基由野生型G突变成A的剪接位点新突变。神经电生理检查显示了右腓总神经的CMAP波幅下降。运动诱发电位(MEP)显示了AT和FMI的CMCT明显延长。MR显示了胸髓从T1到T10均呈不同程度的萎缩,但脊髓内未见明显异常信号。
3.在家系3中,根据等位基因共享和突变筛选的方法,发现SPAST基因第8外显子1168位碱基,由野生型A突变成G,使386号密码子由蛋氨酸变为缬氨酸。
4.在家系4中,根据等位基因共享分析和全基因组扫描和连锁分析的方法,把该家系定位于SPG19(9q33.1-9q34.11),与已知的SPGl9位点相比,缩小了定位区域,为克隆SPG19的候选基因缩小了范围。
5.在家系5中,根据等位基因共享分析的方法和连锁分析的方法,排除了已知的单纯型的ARHSP的全部疾病位点,为找到导致该家系的致病基因缩小了范围。
结论:
1.我们的结果支持了NIPA1,REEP1,SPAST基因突变可以引起ADHSP,进一步证明了HSP遗传异质性。
2.阐述了在SPG6,SPG31,SPG4中基因型和表型的关系,丰富HSP致病基因的突变谱。我们的结果提示了电生理技术和MRI可做为一些SPG亚型的早期诊断指标。
3.通过全基因组扫描,把一个ADHSP家系定位于SPG19,在中国的HSP家系中首次发现了该致病位点,并且缩小了候选基因的区域,为发现克隆SPG19候选致病基因提供基础。
4.根据等位基因共享和连锁分析的方法,在一个ARHSP中,排除了已知的单纯型ARHSP的全部疾病位点,为发现新ARHSP疾病位点提供基础。
第二部分:REEP1和ZFYVE27基因功能的初步研究
研究目的:
遗传性痉挛性截瘫是一组上运动神经变性疾病,其特点是下肢渐进性的痉挛,是由皮质脊髓束运动轴突变性和发育异常引起的。SPG31(REEP1)和SPG33(ZFYVE27)基因突变可引起常染色体显性遗传的遗传性痉挛性截瘫。利用斑马鱼为动物模型,研究reepl和zfyve27在斑马鱼胚胎发育中的作用,用morpholino knock down reepl和zfyve27构建斑马鱼的截瘫模型,对遗传性痉挛性截瘫发病机制做初步探讨,为研究遗传性痉挛性截瘫发病机制提供了基础。
研究方法:
1.斑马鱼reepl和zfyve27基因的克隆。
2.mRNA原位杂交和RT-PCR方法确定了斑马鱼胚胎发育中的reepl和zfyve27的时空表达方式。
3.设计morpholino-靶向反义寡核苷酸,通过显微注射技术导入受精卵联合运用显微镜检术和RT-PCR技术证实了reepl和zfyve27 morpholino的特异性和在体内功效。观察morpholino knockdown后是否引起的表型缺陷。
研究结果:
1.RT-PCR结果表明reepl基因在1细胞期有表达;合子基因从体节期开始表达之后逐渐增加,24～30hpf时持续高表达,此后表达水平适中,至5dpf时有所回升。zfyve27在1细胞期表达水平高,之后递减至50%外包期回升,至bud期又有高水平表达;之后递减,从14体节期至4dpf内表达水平适中且稳定,5dpf表达量有所回升。
2.原位杂交的显示reepl基因在体节期时表达于肌节中,24hpf时可见高表达;之后逐渐由体节转移至脑部组织,2dpf时体节中还有少量表达;5dpf时该基因在脑部组织和脊索中有表达,存体节中无明显表达。zfyve27从lcell至体节期一直为泛表达,24hpf除脊索外均有表达,之后表达部位逐渐集中在头部和内胚层,5dpf表达在头部神经组织、内胚层器官、脊索。
3.reepl和zfyve27 morpholino knock down后均显示了围心腔扩大,尾部卷曲,严重得损害了斑马鱼正常游动的能力的表型,整个表型按照严重程度主要分为三类。正常,畸形(尾巴轻微卷曲和严重卷曲),死亡。表型明显3dpf时,野生型斑马鱼尾巴是直的,注射reepl morpholino显示在339条鱼中,有165条(48.67%)出现畸形(尾巴轻微卷曲和严重卷曲),77(22.71%)死亡。注射zfyve27 morpholino显示在233条鱼中,有108条(46.35%)出现畸形,26(11.16%)死亡。注射morpholino鱼与注射controlmorpholino鱼相比表型组分布有明显的差别(P＜0.001)。
4.免疫组化用抗TUBLIN染色分析胚胎生长轴突,我们发现脊髓运动神经元发育不正常。注射zfyve27 morpholino的,运动神经元轴突短和不正常的分支,脊髓神经元之间的结构也不同,这说明缺少zfyve27基因似乎妨碍轴突的生长。
结论:
1.reepl在斑马鱼胚胎发育过程中,其合子基因体节期开始表达,24～30hpf时持续高表达,此后表达水平适中,至5dpf时有所回升,原位杂交显示reepl基因在从体节期到24hpf主要在肌节中表达;之后逐渐由体节转移至脑部组织,5dpf时该基因在脑部组织和脊索中有表达,在体节中无明显表达。reepl特异性的时空表达pattern说明了reepl在斑马鱼胚胎发育过程中可能起重要的作用。
2.zfyve27从1细胞期表达水平高,之后递减。至50%外包期表达回升,至4dpf内表达水平适中且稳定,5dpf表达量有所回升。原位杂交显示zfyve27从lcell至体节期一直为泛表达,24hpf除脊索外均有表达,之后表达部位逐渐集中在头部和内胚层,5dpf表达在头部神经组织、内胚层器官、脊索。zfyve27特异性的时空表达pattern说明了zfyve27在斑马鱼胚胎发育过程中可能起重要的作用。
3.reepl和zfyve27 morpholino knockdown产生了斑马鱼运动神经元发育不正常,尾部卷曲,游动能力受损的表型。我们的结果说明了reepl和zfyve27是促进轴突生长发育所必需。
4.我们首次用reepl和zfyve27 morpholino knockdown构建了斑马鱼的截瘫模型。这种疾病表型为系统详细地分析遗传性痉挛性截瘫的病理机制奠定基础。
Backrounds:
Hereditary spastic paraplegia(HSP) is a collection of neurological disorders characterised by developmental failure or degeneration of motor axons in the corticospinal tract and progressive lower limb spasticity.Clinically,HSP are divided into pure forms(symptoms confined to lower extremity weakness,bladder disturbance,and to a lesser extent impaired position sense in the legs) or complicated forms when additional neurologic deficits are present,such as optic neuropathy,retinopathy,extra pyramidal,disturbance,dementia, ataxia,ichthyosis,mental retardation,deafness,and epilepsy.HSP can be inherited in an autosomal dominant(ADHSP),an autosomal recessive(ARHSP) or an X-chromosome-linked(XHSP) manner.HSP is genetically heterogeneous,and 15 genes have been cloned although the 33 disease loci have been identified.
Objects:
To describe five Shandong province kindred with ADHSP and ARHSP and detect which gene mutation involved and analyze whether there are genotype-phenotype correlation in clinical character respectively.
Methods:
Linkage analysis and mutation detection were performed.And then,clinical analysis, electrophysiological examination and magnetic resonance imaging(MRI) of brain and spinal cord were also performed in all affected individual of the family 1 and two affected of family 2.
Results:
1.Linkage analysis confined family family 1 to SPG6(N1PA1) with positive Iod scores obtained for the D15S817 and D15S541.Every effected individual had a c316(G106R) mutation in the NIPA1 gene.Neurophysiological examination revealed in most of patients the decreased amplitude of compound muscle action potentials(CMAP) to the tibialis and perineus nerve in motor nerve.Sensory nerve action potential(SNAP) to the tibialis nerve was not elicited in most of patients.Central motor conduction time(CMCT) to abductor pollicis brevis muscle(APB) and the first metatarsal interosseus muscle(FMI) and the anterior tibial muscle(TA) after by transcraniai magnetic stimulation were either absent or clearly prolonged in all patients.MRI of spinal cord showed different levels of atrophy was found in every affected individual.In significant atrophy segments of spinal cord,all the patients revealed distinct grey and white matter boundary.The lesions present clear boundary,median zygomorphic,spot or patch increased signal on transverse axis T2W1 and continuous longitudinal strip increased signal on the anteroposterior axis.
2.Linkage analysis confined family 2 to SPG31(reepl) with positive iod scores obtained for the D2S2951 and D2S3333.A novel splice-site mutation(REEPI c417+1g＞a) was identified.Neurophysiological examination revealed in two patients the decreased amplitude of CMAP to the right perineus nerve in motor nerve.Central motor conduction time to the first metatarsal interosseus and anterior tibial muscles were clearly prolonged.MR showed that thoracic cord atrophy was found from T1 to T10 with no abvious abnormal signal.
3.A known mutation,namely SPAST c1168(M3861),was identified by allele sharing and mutation detection in the family 3.
4.Family 4 was confined to SPGI9(9q33.1-9q34.11) by allele sharing and linkage analysis and a genome-wide scan.We curtailed the scope of cloning candidate gene of SPG19 compared with known SPG19 locus.
5.The reported disease locus relative to pure ARHSP had been excluded by allele sharing and linkage analysis.Therefore,we curtailed the scope of gene mapping in this family.
Conclusions:
1.Our study supports evidence that mutations in NIPA1、reepl and SPAST cause ADHSP and demonstrates further allelic heterogeneity.
2.We analyzing genotype-phenotype correlation of SPG6、SPG31 and SPG4.It also suggests that electrophysiological techniques and MR1 could be used to diagnose subtype of HSP early.
3.We maped an ADHSP to SPG19(9q33.1-9q34.11) by a genome-wide scan.We found SPG19 locus in Chinese family firstly and curtailed the scope of cloning candidate gene of SPG 19.
4.We exclude the reported disease locus relative to pure ARHSP by allele sharing and linkage analysis in the family 5.Therefore,we curtailed the scope of gene mapping in this family and lay basis on identifying a novel pure ARHSP locus.
Objects:
Hereditary spastic paraplegia(HSP) is a collection of neurological disorders characterised by developmental failure or degeneration of motor axons in the corticospinal tract and progressive lower limb spasticity.Mutations in the SPG31(reepl) and SPG33(ZFYVE27) can cause autosomal dominant hereditary spastic paraplegia.To explore the developmental role of reepl and zfyve27 using the zebrafish model and construct the model of spastic paraplegia with morpholino knocking down reepl and zfyve27 and lay the basis on study of the pathogenesy of hereditary spastic paraplegia.
Methods:
1.To clone reepl and zfyve27 ofzebrafish.
2.To determine expression pattern of reepl and zfyve27 in the development of zebrafish embryo by mRNA insitu-hybridization and RT-PCR.
3.To design morpholino-modified antisense oligonucleotides and micro-inject into zygote of zebrafish together with confirming specificity and efficiency in vivo of reepl and zfyve27 morpholino.We observe weather phenotype associated with disease exist after morpholino knockdown.
Results:
1.RT-PCR of reepl indicated expression in 1-cell stage;zygocyte gene began to express in somite stage,then turned to increase expression gradually and kept high in 24～30hpf.After medium expression,it came to increase in 5dpf.RT-PCR of zfyve27 indicated high expression in 1-cell stage;it began to decrease expression after 1-cell stage and began to increase in 50%epiboly stage,to bud stage zfyve27 showed high expression and begin to decrease progressively after then.The zfyve27 had stable and medium expression from 14 somite stage to 4dpf,and began to increase expression in 5dpf.
2.In situ hybridization of reepl mRNA indicated the myocomma expression domains in somite stage,high expression in 24hpf;and then expression gradually transfered from somite to brain,reepl showed small expression in somite in 2dpf,while no clear expression existed in somite in 5dpf when reepl mainly expressed in brain tissue and notochord.In situ hybridization of zfyve27 mRNA indicated the general expression domains from 1 cell stage to somite stage.It expressed widespread in vivo except notochord in 24hpf,then turned to concentrate gradually expression in brain and endoblast;zfyve27 expressed in nerve tissue of brain,endoblast and notochord in 5dpf.
3.Morpholino oligonucleotide knockdown of the reepl and zfyve27 protein ortholog in zebrafish resulted in an enlarged heart cavity,along with a curly-tail phenotype that severely impaired the ability of the fish to swim properly.The overall phenotype ranged in severity and was classified in three major groups:normal,deformation,(slightly curly and severely curly),and death.This phenotype was clearly visible at 3 day post fertilization(dpf) when wildtype zebrafish are with a straight tail.Injection of the reepl morpholino resulted in 165 (48.67%) of 339 fish with deformation and 77(22.71%) with a death.Injection of the zfyve27 morpholino resulted in 108(46.35%) of 233 fish with deformation and 26(11.16%) with a death.The reepl and zfyve27 morpholino fish had a significantly different distribution of phenotypic groups compared with those with control morpholino injections (P＜0.001).
4.On histochemical analysis of the embryos by use o f an antiacetylated tubulinstain for growing axons,we found that the motor neurons in the spinal cord did not develop normally. Motor neuron axons in fish injected with zfyve27 gene alone were shorter and showed abnormal branching.The structure of interneurons in the spinal cord was also different.The absence of the zfyve27 gene or mutations in this gene during early development thus seemed to hamper axonal outgrowth.
Conclusions:
1.reepl zygocyte gene began to express in somite stage,kept high in 24～30hpf.After medium expression,it came to increase in 5dpf.In situ hybridization of reepl indicated myocomma expression domains frome somite stage to 24hpf and then expression gradually transfered from somite to brain.While no clear expression existed in somite in 5dpf when reepl mainly expressed in brain tissue and notochord.Expression pattern of reepl reveal requirement development of nerve system during embryonic development
2.zfyve27 indicated high expression in 1-cell stage;it began to decrease expression after 1-cell stage and began to increase in 50%epiboly stage,to bud stage zfyve27 showed high expression and begin to decrease progressively after then.The zfyve27 had stable and medium expression from 14 somite stage to 4dpf,and began to increase expression in 5dpf. In situ hybridization of zfyve27 indicated the general expression domains from 1 cell stage to somite stage.It expressed widespread in vivo except notochord in 24hpf,then turned to concentrate gradually expression in brain and endoblast;zfyve27 expressed in nerve tissue of brain,endoblast and notochord in 5dpf.Expression pattern of zfyve27 reveal requirement development of nerve system during embryonic development.
3.reepl and zfyve27 morpholino knockdown result in phenotypes such as curly-tail,the impaired ability to swim and abnormal development of motor neuron.Our results reveal a critical requirement for reepl and zfyve27 to promote axonal outgrowth during embryonic development.
4.We firstly construct HPS model by zebrafish with reepl and zfyve27 morpholino knockdown.The zebrafish embryo was used as a novel model system in which to dissect the pathogenetic mechanisms underlying HSP.
研究背景:
遗传性痉挛性截瘫(Hereditary Spastic Paraplegias,HSP)是一组上运动神经变性疾病,其特点是下肢渐进性的痉挛,是由皮质脊髓束运动轴突变性和发育异常引起的。按临床表现可分为单纯型和复杂型,单纯型只表现为进行性双下肢肌张力增高和无力,合并脊髓外损害,如肌肉萎缩、精神发育迟滞、共济失调、多发性神经病、视神经萎缩、视网膜色素变性、耳聋、锥体外系等症状的称为复杂型。按遗传方式分为常染色体显性遗传(ADHSP)、常染色体隐性遗传(ARHSP)X连锁隐性遗传(XRHSP)。遗传性痉挛性截瘫具有很强的异质性,到目前为止,虽然已发现33个HSP疾病基因相关位点,但是只有其中15个疾病基因已被克隆。
研究目的:
研究来自山东5个ADHSP和ARHSP家系,进行致病基因定位和突变筛查,并且分析各型HSP家系基因型和表型的关系,
研究方法:
利用等位基因共享分析、全基因组扫描、连锁分析、定位候选克隆策略,进行致病基因定位与突变筛选。对家系1全部6个患者,家系2的2个患者,进行临床表型分析,电生理和脊髓与大脑的MR的扫描。
研究结果:
1.在家系1中,连锁分析显示微卫星分子标记D15S817和D15S541与致病基因成立连锁关系,定位于SPG6(NIPA1基因)。突变筛查发现NIPA1基因第3外显子第316位碱基野生型G突变成C(G→C),造成106号密码子由Gly→Arg。神经电生理检查显示了大多数患者运动神经的胫神经和腓总神经的混合肌肉动作电位(CMAP)波幅下降。胫神经感觉神经动作电位(SNAP)大多数没有引出。所有患者MEP显示了胫前肌(AT)和第一趾骨间肌(FMI)的中枢运动传导时间(CMCT)或者没有引出,或者明显延长。脊髓MRI显示了脊髓呈不同程度萎缩,相应脊髓节段灰白质分界显示清楚,横轴位T2WI上灰质呈边界清楚、左右对称的点状或点片状高信号,矢状位上表现为连续纵行的条状高信号。灰白质均受累,蛛网膜下腔扩大。
2.在家系2中,连锁分析显示微卫星分子标记D2S2951与D2S2333与致病基因成立连锁关系,定位于SPG31(REEP1基因)。突变筛查发现REEP1基因第5外显子受体位第417+1位碱基由野生型G突变成A的剪接位点新突变。神经电生理检查显示了右腓总神经的CMAP波幅下降。运动诱发电位(MEP)显示了AT和FMI的CMCT明显延长。MR显示了胸髓从T1到T10均呈不同程度的萎缩,但脊髓内未见明显异常信号。
3.在家系3中,根据等位基因共享和突变筛选的方法,发现SPAST基因第8外显子1168位碱基,由野生型A突变成G,使386号密码子由蛋氨酸变为缬氨酸。
4.在家系4中,根据等位基因共享分析和全基因组扫描和连锁分析的方法,把该家系定位于SPG19(9q33.1-9q34.11),与已知的SPGl9位点相比,缩小了定位区域,为克隆SPG19的候选基因缩小了范围。
5.在家系5中,根据等位基因共享分析的方法和连锁分析的方法,排除了已知的单纯型的ARHSP的全部疾病位点,为找到导致该家系的致病基因缩小了范围。
结论:
1.我们的结果支持了NIPA1,REEP1,SPAST基因突变可以引起ADHSP,进一步证明了HSP遗传异质性。
2.阐述了在SPG6,SPG31,SPG4中基因型和表型的关系,丰富HSP致病基因的突变谱。我们的结果提示了电生理技术和MRI可做为一些SPG亚型的早期诊断指标。
3.通过全基因组扫描,把一个ADHSP家系定位于SPG19,在中国的HSP家系中首次发现了该致病位点,并且缩小了候选基因的区域,为发现克隆SPG19候选致病基因提供基础。
4.根据等位基因共享和连锁分析的方法,在一个ARHSP中,排除了已知的单纯型ARHSP的全部疾病位点,为发现新ARHSP疾病位点提供基础。
第二部分:REEP1和ZFYVE27基因功能的初步研究
研究目的:
遗传性痉挛性截瘫是一组上运动神经变性疾病,其特点是下肢渐进性的痉挛,是由皮质脊髓束运动轴突变性和发育异常引起的。SPG31(REEP1)和SPG33(ZFYVE27)基因突变可引起常染色体显性遗传的遗传性痉挛性截瘫。利用斑马鱼为动物模型,研究reepl和zfyve27在斑马鱼胚胎发育中的作用,用morpholino knock down reepl和zfyve27构建斑马鱼的截瘫模型,对遗传性痉挛性截瘫发病机制做初步探讨,为研究遗传性痉挛性截瘫发病机制提供了基础。
研究方法:
1.斑马鱼reepl和zfyve27基因的克隆。
2.mRNA原位杂交和RT-PCR方法确定了斑马鱼胚胎发育中的reepl和zfyve27的时空表达方式。
3.设计morpholino-靶向反义寡核苷酸,通过显微注射技术导入受精卵联合运用显微镜检术和RT-PCR技术证实了reepl和zfyve27 morpholino的特异性和在体内功效。观察morpholino knockdown后是否引起的表型缺陷。
研究结果:
1.RT-PCR结果表明reepl基因在1细胞期有表达;合子基因从体节期开始表达之后逐渐增加,24～30hpf时持续高表达,此后表达水平适中,至5dpf时有所回升。zfyve27在1细胞期表达水平高,之后递减至50%外包期回升,至bud期又有高水平表达;之后递减,从14体节期至4dpf内表达水平适中且稳定,5dpf表达量有所回升。
2.原位杂交的显示reepl基因在体节期时表达于肌节中,24hpf时可见高表达;之后逐渐由体节转移至脑部组织,2dpf时体节中还有少量表达;5dpf时该基因在脑部组织和脊索中有表达,存体节中无明显表达。zfyve27从lcell至体节期一直为泛表达,24hpf除脊索外均有表达,之后表达部位逐渐集中在头部和内胚层,5dpf表达在头部神经组织、内胚层器官、脊索。
3.reepl和zfyve27 morpholino knock down后均显示了围心腔扩大,尾部卷曲,严重得损害了斑马鱼正常游动的能力的表型,整个表型按照严重程度主要分为三类。正常,畸形(尾巴轻微卷曲和严重卷曲),死亡。表型明显3dpf时,野生型斑马鱼尾巴是直的,注射reepl morpholino显示在339条鱼中,有165条(48.67%)出现畸形(尾巴轻微卷曲和严重卷曲),77(22.71%)死亡。注射zfyve27 morpholino显示在233条鱼中,有108条(46.35%)出现畸形,26(11.16%)死亡。注射morpholino鱼与注射controlmorpholino鱼相比表型组分布有明显的差别(P＜0.001)。
4.免疫组化用抗TUBLIN染色分析胚胎生长轴突,我们发现脊髓运动神经元发育不正常。注射zfyve27 morpholino的,运动神经元轴突短和不正常的分支,脊髓神经元之间的结构也不同,这说明缺少zfyve27基因似乎妨碍轴突的生长。
结论:
1.reepl在斑马鱼胚胎发育过程中,其合子基因体节期开始表达,24～30hpf时持续高表达,此后表达水平适中,至5dpf时有所回升,原位杂交显示reepl基因在从体节期到24hpf主要在肌节中表达;之后逐渐由体节转移至脑部组织,5dpf时该基因在脑部组织和脊索中有表达,在体节中无明显表达。reepl特异性的时空表达pattern说明了reepl在斑马鱼胚胎发育过程中可能起重要的作用。
2.zfyve27从1细胞期表达水平高,之后递减。至50%外包期表达回升,至4dpf内表达水平适中且稳定,5dpf表达量有所回升。原位杂交显示zfyve27从lcell至体节期一直为泛表达,24hpf除脊索外均有表达,之后表达部位逐渐集中在头部和内胚层,5dpf表达在头部神经组织、内胚层器官、脊索。zfyve27特异性的时空表达pattern说明了zfyve27在斑马鱼胚胎发育过程中可能起重要的作用。
3.reepl和zfyve27 morpholino knockdown产生了斑马鱼运动神经元发育不正常,尾部卷曲,游动能力受损的表型。我们的结果说明了reepl和zfyve27是促进轴突生长发育所必需。
4.我们首次用reepl和zfyve27 morpholino knockdown构建了斑马鱼的截瘫模型。这种疾病表型为系统详细地分析遗传性痉挛性截瘫的病理机制奠定基础。
Backrounds:
Hereditary spastic paraplegia(HSP) is a collection of neurological disorders characterised by developmental failure or degeneration of motor axons in the corticospinal tract and progressive lower limb spasticity.Clinically,HSP are divided into pure forms(symptoms confined to lower extremity weakness,bladder disturbance,and to a lesser extent impaired position sense in the legs) or complicated forms when additional neurologic deficits are present,such as optic neuropathy,retinopathy,extra pyramidal,disturbance,dementia, ataxia,ichthyosis,mental retardation,deafness,and epilepsy.HSP can be inherited in an autosomal dominant(ADHSP),an autosomal recessive(ARHSP) or an X-chromosome-linked(XHSP) manner.HSP is genetically heterogeneous,and 15 genes have been cloned although the 33 disease loci have been identified.
Objects:
To describe five Shandong province kindred with ADHSP and ARHSP and detect which gene mutation involved and analyze whether there are genotype-phenotype correlation in clinical character respectively.
Methods:
Linkage analysis and mutation detection were performed.And then,clinical analysis, electrophysiological examination and magnetic resonance imaging(MRI) of brain and spinal cord were also performed in all affected individual of the family 1 and two affected of family 2.
Results:
1.Linkage analysis confined family family 1 to SPG6(N1PA1) with positive Iod scores obtained for the D15S817 and D15S541.Every effected individual had a c316(G106R) mutation in the NIPA1 gene.Neurophysiological examination revealed in most of patients the decreased amplitude of compound muscle action potentials(CMAP) to the tibialis and perineus nerve in motor nerve.Sensory nerve action potential(SNAP) to the tibialis nerve was not elicited in most of patients.Central motor conduction time(CMCT) to abductor pollicis brevis muscle(APB) and the first metatarsal interosseus muscle(FMI) and the anterior tibial muscle(TA) after by transcraniai magnetic stimulation were either absent or clearly prolonged in all patients.MRI of spinal cord showed different levels of atrophy was found in every affected individual.In significant atrophy segments of spinal cord,all the patients revealed distinct grey and white matter boundary.The lesions present clear boundary,median zygomorphic,spot or patch increased signal on transverse axis T2W1 and continuous longitudinal strip increased signal on the anteroposterior axis.
2.Linkage analysis confined family 2 to SPG31(reepl) with positive iod scores obtained for the D2S2951 and D2S3333.A novel splice-site mutation(REEPI c417+1g＞a) was identified.Neurophysiological examination revealed in two patients the decreased amplitude of CMAP to the right perineus nerve in motor nerve.Central motor conduction time to the first metatarsal interosseus and anterior tibial muscles were clearly prolonged.MR showed that thoracic cord atrophy was found from T1 to T10 with no abvious abnormal signal.
3.A known mutation,namely SPAST c1168(M3861),was identified by allele sharing and mutation detection in the family 3.
4.Family 4 was confined to SPGI9(9q33.1-9q34.11) by allele sharing and linkage analysis and a genome-wide scan.We curtailed the scope of cloning candidate gene of SPG19 compared with known SPG19 locus.
5.The reported disease locus relative to pure ARHSP had been excluded by allele sharing and linkage analysis.Therefore,we curtailed the scope of gene mapping in this family.
Conclusions:
1.Our study supports evidence that mutations in NIPA1、reepl and SPAST cause ADHSP and demonstrates further allelic heterogeneity.
2.We analyzing genotype-phenotype correlation of SPG6、SPG31 and SPG4.It also suggests that electrophysiological techniques and MR1 could be used to diagnose subtype of HSP early.
3.We maped an ADHSP to SPG19(9q33.1-9q34.11) by a genome-wide scan.We found SPG19 locus in Chinese family firstly and curtailed the scope of cloning candidate gene of SPG 19.
4.We exclude the reported disease locus relative to pure ARHSP by allele sharing and linkage analysis in the family 5.Therefore,we curtailed the scope of gene mapping in this family and lay basis on identifying a novel pure ARHSP locus.
Objects:
Hereditary spastic paraplegia(HSP) is a collection of neurological disorders characterised by developmental failure or degeneration of motor axons in the corticospinal tract and progressive lower limb spasticity.Mutations in the SPG31(reepl) and SPG33(ZFYVE27) can cause autosomal dominant hereditary spastic paraplegia.To explore the developmental role of reepl and zfyve27 using the zebrafish model and construct the model of spastic paraplegia with morpholino knocking down reepl and zfyve27 and lay the basis on study of the pathogenesy of hereditary spastic paraplegia.
Methods:
1.To clone reepl and zfyve27 ofzebrafish.
2.To determine expression pattern of reepl and zfyve27 in the development of zebrafish embryo by mRNA insitu-hybridization and RT-PCR.
3.To design morpholino-modified antisense oligonucleotides and micro-inject into zygote of zebrafish together with confirming specificity and efficiency in vivo of reepl and zfyve27 morpholino.We observe weather phenotype associated with disease exist after morpholino knockdown.
Results:
1.RT-PCR of reepl indicated expression in 1-cell stage;zygocyte gene began to express in somite stage,then turned to increase expression gradually and kept high in 24～30hpf.After medium expression,it came to increase in 5dpf.RT-PCR of zfyve27 indicated high expression in 1-cell stage;it began to decrease expression after 1-cell stage and began to increase in 50%epiboly stage,to bud stage zfyve27 showed high expression and begin to decrease progressively after then.The zfyve27 had stable and medium expression from 14 somite stage to 4dpf,and began to increase expression in 5dpf.
2.In situ hybridization of reepl mRNA indicated the myocomma expression domains in somite stage,high expression in 24hpf;and then expression gradually transfered from somite to brain,reepl showed small expression in somite in 2dpf,while no clear expression existed in somite in 5dpf when reepl mainly expressed in brain tissue and notochord.In situ hybridization of zfyve27 mRNA indicated the general expression domains from 1 cell stage to somite stage.It expressed widespread in vivo except notochord in 24hpf,then turned to concentrate gradually expression in brain and endoblast;zfyve27 expressed in nerve tissue of brain,endoblast and notochord in 5dpf.
3.Morpholino oligonucleotide knockdown of the reepl and zfyve27 protein ortholog in zebrafish resulted in an enlarged heart cavity,along with a curly-tail phenotype that severely impaired the ability of the fish to swim properly.The overall phenotype ranged in severity and was classified in three major groups:normal,deformation,(slightly curly and severely curly),and death.This phenotype was clearly visible at 3 day post fertilization(dpf) when wildtype zebrafish are with a straight tail.Injection of the reepl morpholino resulted in 165 (48.67%) of 339 fish with deformation and 77(22.71%) with a death.Injection of the zfyve27 morpholino resulted in 108(46.35%) of 233 fish with deformation and 26(11.16%) with a death.The reepl and zfyve27 morpholino fish had a significantly different distribution of phenotypic groups compared with those with control morpholino injections (P＜0.001).
4.On histochemical analysis of the embryos by use o f an antiacetylated tubulinstain for growing axons,we found that the motor neurons in the spinal cord did not develop normally. Motor neuron axons in fish injected with zfyve27 gene alone were shorter and showed abnormal branching.The structure of interneurons in the spinal cord was also different.The absence of the zfyve27 gene or mutations in this gene during early development thus seemed to hamper axonal outgrowth.
Conclusions:
1.reepl zygocyte gene began to express in somite stage,kept high in 24～30hpf.After medium expression,it came to increase in 5dpf.In situ hybridization of reepl indicated myocomma expression domains frome somite stage to 24hpf and then expression gradually transfered from somite to brain.While no clear expression existed in somite in 5dpf when reepl mainly expressed in brain tissue and notochord.Expression pattern of reepl reveal requirement development of nerve system during embryonic development
2.zfyve27 indicated high expression in 1-cell stage;it began to decrease expression after 1-cell stage and began to increase in 50%epiboly stage,to bud stage zfyve27 showed high expression and begin to decrease progressively after then.The zfyve27 had stable and medium expression from 14 somite stage to 4dpf,and began to increase expression in 5dpf. In situ hybridization of zfyve27 indicated the general expression domains from 1 cell stage to somite stage.It expressed widespread in vivo except notochord in 24hpf,then turned to concentrate gradually expression in brain and endoblast;zfyve27 expressed in nerve tissue of brain,endoblast and notochord in 5dpf.Expression pattern of zfyve27 reveal requirement development of nerve system during embryonic development.
3.reepl and zfyve27 morpholino knockdown result in phenotypes such as curly-tail,the impaired ability to swim and abnormal development of motor neuron.Our results reveal a critical requirement for reepl and zfyve27 to promote axonal outgrowth during embryonic development.
4.We firstly construct HPS model by zebrafish with reepl and zfyve27 morpholino knockdown.The zebrafish embryo was used as a novel model system in which to dissect the pathogenetic mechanisms underlying HSP.
引文
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