肌萎缩侧索硬化多态性关联分析及基因突变研究
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摘要
肌萎缩侧索硬化是由脑和脊髓运动神经元进行性退变引起的一种致死性瘫痪性疾病,散发性ALS占患病人群的近90%。ALS被认为是一种复杂性疾病。目前已有数个关于ALS的全基因组关联分析研究,并先后报道若干与增加ALS发病风险相关的单核苷酸多态性(SNP)位点。TARDBP基因突变存在于约0.5-3%的ALS人群中,很可能是ALS的又一易感基因。
目的：在以中国人群组成的样本中研究和增加SALS致病风险相关的SNP；筛查我院SALS患者人群中TARDBP基因6号外显子蛋白编码区突变。
方法：提取样本外周血基因组DNA,进行病例组(86例)和对照组(94例)年龄性别匹配,质谱法分型筛选出的SNP位点并进行关联分析；PCR扩增TARDBP基因6号外显子蛋白编码区,高分辨熔解法进行PCR产物的基因分型。
结果：
1、由中国人群组成的86例患者与94例对照组完成rs6700125、rs10260404. rs1942239、rs2279812、rs2405657、rs558889、rs6922711、rs9351470共8个SNP位点的基因分型,统计分析后无显著性差异。其中rs1942239、rs6922711在HapMap中欧洲人与中国人MAF接近,合并Cronin等人的研究数据显示rs1942239的P值减小,关联性增强。
2、我院收集的89例SALS患者的TARDBP基因6号外显子蛋白编码区突变HRM法筛查发现两例TARDBP基因序列的1098位C突变为G,但是编码氨基酸不变且不影响剪切,考虑为同义突变,基因库及相关研究未见该突变的报道。
结论：
1、本研究为国际ALS的SNP数据库增加了亚洲人群的数据。在中国人群为样本的病例对照研究中,未发现某一特定SNP和增加SALS致病风险相关,合并Cronin研究数据后GALNT1(rs1942239邻近基因)与增加SALS致病风险相关。
2、我院89例SALS患者未发现TARDBP基因的错义突变,结果提示在中国人群中TARDBP基因可能不是SALS的主要易感基因。
Amyotrophic lateral sclerosis (ALS) is a progressive paralytic disorder resulting from the degeneration of motor neurons in brain and spinal cord. Sporadic ALS (SALS) accounts for majority of patients. ALS is a kind of complex disorder. There were several SNPs reported to be associated with SALS in recently published articles about genome-wide association (GWA) of ALS. Transactive response DNA binding protein(TARDBP) gene mutations in ALS are responsible for about0.5%-3%of ALS cases. Mutation of TARDBP gene may be another common cause of sporadic ALS.
OBJECTIVE:We study the genome polymorphism in SALS of Chinese origin; search for TRADBP mutations in SALS cases.
METHODS:We recruited86individuals with SALS and94matched controls for our study, extracted genomic DNA from blood samples. Alleles were determined by a MALDI-TOF based approach followed by association analysis. The coding region of TARDBP exon6, was amplified by polymerase chain reaction (PCR). The PCR products were genotyped using high-resolution melting technology (HRM).
RESULTS:
1. Individual genotype data for8SNPs in Chinese population showed no significant association with SALS. On analysis of combined genotyping data, rs1942239gained in strength of allelic association.
2. We observe one silent mutation (1098C>G) in2Chinese individuals with SALS. The mutation was not reported before and less likely to be pathogenic. No missense mutation is found in89Chinese individuals with SALS.
CONCLUSIONS:
1. Research provides new data of Asian people for ALS GWA. No SNP is definitively associated with increased risk of developing disease in Chinese population. Variants of GALNT1(near SNP rs1942239) may confer susceptibility to sporadic ALS based on the combined data.
2. No TARDBP missense mutation is found in89Chinese cases. Our data indicates that genetic variation in TARDBP may be not a common cause of sporadic ALS in Chinese.
目的：在以中国人群组成的样本中研究和增加SALS致病风险相关的SNP；筛查我院SALS患者人群中TARDBP基因6号外显子蛋白编码区突变。
方法：提取样本外周血基因组DNA,进行病例组(86例)和对照组(94例)年龄性别匹配,质谱法分型筛选出的SNP位点并进行关联分析；PCR扩增TARDBP基因6号外显子蛋白编码区,高分辨熔解法进行PCR产物的基因分型。
结果：
1、由中国人群组成的86例患者与94例对照组完成rs6700125、rs10260404. rs1942239、rs2279812、rs2405657、rs558889、rs6922711、rs9351470共8个SNP位点的基因分型,统计分析后无显著性差异。其中rs1942239、rs6922711在HapMap中欧洲人与中国人MAF接近,合并Cronin等人的研究数据显示rs1942239的P值减小,关联性增强。
2、我院收集的89例SALS患者的TARDBP基因6号外显子蛋白编码区突变HRM法筛查发现两例TARDBP基因序列的1098位C突变为G,但是编码氨基酸不变且不影响剪切,考虑为同义突变,基因库及相关研究未见该突变的报道。
结论：
1、本研究为国际ALS的SNP数据库增加了亚洲人群的数据。在中国人群为样本的病例对照研究中,未发现某一特定SNP和增加SALS致病风险相关,合并Cronin研究数据后GALNT1(rs1942239邻近基因)与增加SALS致病风险相关。
2、我院89例SALS患者未发现TARDBP基因的错义突变,结果提示在中国人群中TARDBP基因可能不是SALS的主要易感基因。
Amyotrophic lateral sclerosis (ALS) is a progressive paralytic disorder resulting from the degeneration of motor neurons in brain and spinal cord. Sporadic ALS (SALS) accounts for majority of patients. ALS is a kind of complex disorder. There were several SNPs reported to be associated with SALS in recently published articles about genome-wide association (GWA) of ALS. Transactive response DNA binding protein(TARDBP) gene mutations in ALS are responsible for about0.5%-3%of ALS cases. Mutation of TARDBP gene may be another common cause of sporadic ALS.
OBJECTIVE:We study the genome polymorphism in SALS of Chinese origin; search for TRADBP mutations in SALS cases.
METHODS:We recruited86individuals with SALS and94matched controls for our study, extracted genomic DNA from blood samples. Alleles were determined by a MALDI-TOF based approach followed by association analysis. The coding region of TARDBP exon6, was amplified by polymerase chain reaction (PCR). The PCR products were genotyped using high-resolution melting technology (HRM).
RESULTS:
1. Individual genotype data for8SNPs in Chinese population showed no significant association with SALS. On analysis of combined genotyping data, rs1942239gained in strength of allelic association.
2. We observe one silent mutation (1098C>G) in2Chinese individuals with SALS. The mutation was not reported before and less likely to be pathogenic. No missense mutation is found in89Chinese individuals with SALS.
CONCLUSIONS:
1. Research provides new data of Asian people for ALS GWA. No SNP is definitively associated with increased risk of developing disease in Chinese population. Variants of GALNT1(near SNP rs1942239) may confer susceptibility to sporadic ALS based on the combined data.
2. No TARDBP missense mutation is found in89Chinese cases. Our data indicates that genetic variation in TARDBP may be not a common cause of sporadic ALS in Chinese.
引文
1 张莉红,李晓光,崔丽英.肌萎缩侧索硬化与超氧化物歧化酶1基因突变研究进展.中华神经科杂志,2007,40：65-67.
2 Simpson CL, Al-Chalabi A. Amyotrophic lateral sclerosis as a complex genetic disease. Biochim Biophys Acta,2006,1762:973-985.
3 Eberle MA, Ng PC, Kuhn K, et al. Power to detect risk alleles using genome-wide tag snp panels. PLoS Genet,2007,3:1827-1837.
4 Dunckley T, Huentelman MJ, Craig DW, et al. Whole-genome analysis of sporadic amyotrophic lateral sclerosis. N Engl J Med,2007,357:775-788.
5 Schymick JC, Scholz SW, Fung HC, et al. Genome-wide genotyping in amyotrophic lateral sclerosis and neurologically normal controls:First stage analysis and public release of data. Lancet Neurol,2007,6:322-328.
6 van Es MA, Van Vught PW, Blauw HM, et al. Itpr2 as a susceptibility gene in sporadic amyotrophic lateral sclerosis:A genome-wide association study. Lancet Neurol, 2007,6:869-877.
7 van Es MA, van Vught PW, Blauw HM, et al. Genetic variation in dpp6 is associated with susceptibility to amyotrophic lateral sclerosis. Nat Genet,2008,40:29-31.
8 Cronin S, Berger S, Ding J, et al. A genome-wide association study of sporadic als in a homogenous irish population. Hum Mol Genet,2008,17:768-774.
9 Traynor BJ, Singleton A. Genome-wide association studies and als:Are we there yet? Lancet Neurol,2007,6:841-843.
10 Pusch W, Wurmbach JH, Thiele H, et al. Maldi-tof mass spectrometry-based snp genotyping. Pharmacogenomics,2002,3:537-548.
11 Mackenzie IR, Rademakers R. The role of transactive response DNA-binding protein-43 in amyotrophic lateral sclerosis and frontotemporal dementia. Curr Opin Neurol,2008,21:693-700.
12 Arai T, Hasegawa M, Akiyama H, et al. Tdp-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Biochem Biophys Res Commun,2006,351:602-611.
13 Neumann M, Sampathu DM, Kwong LK, et al. Ubiquitinated tdp-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science,2006, 314:130-133.
14 Gitcho MA, Baloh RH, Chakraverty S, et al. Tdp-43 a315t mutation in familial motor neuron disease. Ann Neurol,2008,63:535-538.
15 Rutherford NJ, Zhang YJ, Baker M, et al. Novel mutations in tardbp (tdp-43) in patients with familial amyotrophic lateral sclerosis. PLoS Genet,2008,4:e1000193.
16 Van Deerlin VM, Leverenz JB, Bekris LM, et al. Tardbp mutations in amyotrophic lateral sclerosis with tdp-43 neuropathology:A genetic and histopathological analysis. Lancet Neurol,2008,7:409-416.
17 Winton MJ, Van Deerlin VM, Kwong LK, et al. A90v tdp-43 variant results in the aberrant localization of tdp-43 in vitro. FEBS Lett,2008,582:2252-2256.
18 Yokoseki A, Shiga A, Tan CF, et al. Tdp-43 mutation in familial amyotrophic lateral sclerosis. Ann Neurol,2008,63:538-542.
19 Sreedharan J, Blair IP, Tripathi VB, et al. Tdp-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science,2008,319:1668-1672.
20 Kabashi E, Valdmanis PN, Dion P, et al. Tardbp mutations in individuals with sporadic and familial amyotrophic lateral sclerosis. Nat Genet,2008,40:572-574.
21 Kuhnlein P, Sperfeld AD, Vanmassenhove B, et al. Two german kindreds with familial amyotrophic lateral sclerosis due to tardbp mutations. Arch Neurol,2008, 65:1185-1189.
22 Daoud H, Valdmanis PN, Kabashi E, et al. Contribution of tardbp mutations to sporadic amyotrophic lateral sclerosis. J Med Genet,2009,46:112-114.
23 Del Bo R, Ghezzi S, Corti S, et al. Tardbp (tdp-43) sequence analysis in patients with familial and sporadic als:Identification of two novel mutations. Eur J Neurol,2009,
24 Corrado L, Ratti A, Gellera C, et al. High frequency of tardbp gene mutations in italian patients with amyotrophic lateral sclerosis. Hum Mutat,2009,30:688-694.
25 Lemmens R, Race V, Hersmus N, et al. Tdp-43 m311 v mutation in familial amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry,2009,80:354-355.
26 Reed GH, Kent JO, Wittwer CT. High-resolution DNA melting analysis for simple and efficient molecular diagnostics. Pharmacogenomics,2007,8:597-608.
27 Cronin, S. Tomik, B. Bradley, D. G, et al. Screening for replication of genome-wide SNP associations in sporadic ALS. Eur J Hum Genet,2008,17:213-218.
28 KIein,R J.Zeiss,C.Chew, E. Y., et al. Complement Factor H Polymorphism in Age-Related Macular Degeneration. Science,2005,308:385-389.
29 Hopitzan, A. A.Baines, A. J.Kordeli, E. Molecular evolution of ankyrin:gain of function in vertebrates by acquisition of an obscurin/titin-binding-related domain. Mol Biol Evol 2006,23:46-55.
30 Stabach, P. R. Devarajan, P. Stankewich, M. C. Ankyrin facilitates intracellular trafficking of alpha1-Na+-K+-ATPase in polarized cells. Am J Physiol Cell Physiol.2008, 295:C1202-14.
31 Guerreiro RJ, Schymick JC, Crews C, et al. Tdp-43 is not a common cause of sporadic amyotrophic lateral sclerosis. PLoS ONE,2008,3:e2450.
1 Miller RG, Mitchell JD, Lyon M, et al. Riluzole for amyotrophic lateral sclerosis (als)/motor neuron disease (mnd). Cochrane Database Syst Rev,2007:CD001447.
2 张莉红,李晓光,崔丽英.肌萎缩侧索硬化与超氧化物歧化酶1基因突变研究进展.中华神经科杂志,2007,40：65-67.
3 van Es MA, Van Vught PW, Blauw HM, et al. Itpr2 as a susceptibility gene in sporadic amyotrophic lateral sclerosis:a genome-wide association study. Lancet Neurol,2007,6: 869-877.
4 Simpson CL, Al-Chalabi A. Amyotrophic lateral sclerosis as a complex genetic disease. Biochim Biophys Acta,2006,1762:973-985.
5 The international hapmap project. Nature,2003,426:789-796.
6 Eberle MA, Ng PC, Kuhn K, et al. Power to detect risk alleles using genome-wide tag snp panels. PLoS Genet,2007,3:1827-1837.
7 Fung HC, Scholz S, Matarin M, et al. Genome-wide genotyping in parkinson's disease and neurologically normal controls:First stage analysis and public release of data. Lancet Neurol,2006,5:911-916.
8 Schymick JC, Scholz SW, Fung HC, et al. Genome-wide genotyping in amyotrophic lateral sclerosis and neurologically normal controls:First stage analysis and public release of data. Lancet Neurol,2007,6:322-328.
9 Dunckley T, Huentelman MJ, Craig DW, et al. Whole-genome analysis of sporadic amyotrophic lateral sclerosis. N Engl J Med,2007,357:775-788.
10 van Es MA, van Vught PW, Blauw HM, et al. Genetic variation in dpp6 is associated with susceptibility to amyotrophic lateral sclerosis. Nat Genet,2008,40:29-31.
I1 Cronin S, Berger S, Ding J, et al. A genome-wide association study of sporadic als in a homogenous irish population. Hum Mol Genet,2008,17:768-774.
12 Bruijn LI, Miller TM, Cleveland DW. Unraveling the mechanisms involved in motor neuron degeneration in als. Annu Rev Neurosci,2004,27:723-749.
13 Nishimura AL, Mitne-Neto M, Silva HC, et al. A mutation in the vesicle-trafficking protein vapb causes late-onset spinal muscular atrophy and amyotrophic lateral sclerosis. Am J Hum Genet,2004,75:822-831.
14 Conrad DF, Jakobsson M, Coop G, et al. A worldwide survey of haplotype variation and linkage disequilibrium in the human genome. Nat Genet,2006,38:1251-1260.
15 Traynor BJ, Singleton A. Genome-wide association studies and als:Are we there yet? Lancet Neurol,2007,6:841-843.
1 张莉红,李晓光,崔丽英.肌萎缩侧索硬化与超氧化物歧化酶1基因突变研究进展.中华神经科杂志,2007,40：65-67.
2林一聪,李晓光,崔丽英.肌萎缩侧索硬化全基因组关联分析及snp研究进展.中华神经科杂志,2009,42：138-141.
3 Mackenzie IR, Rademakers R. The role of transactive response DNA-binding protein-43 in amyotrophic lateral sclerosis and frontotemporal dementia. Curr Opin Neurol,2008,21:693-700.
4 Arai T, Hasegawa M, Akiyama H, et al. Tdp-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Biochem Biophys Res Commun,2006,351:602-611.
5 Neumann M, Sampathu DM, Kwong LK, et al. Ubiquitinated tdp-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science,2006, 314:130-133.
6 Cairns NJ, Neumann M, Bigio EH, et al. Tdp-43 in familial and sporadic frontotemporal lobar degeneration with ubiquitin inclusions. Am J Pathol,2007, 171:227-240.
7 Mackenzie IR, Bigio EH, Ince PG, et al. Pathological tdp-43 distinguishes sporadic amyotrophic lateral sclerosis from amyotrophic lateral sclerosis with sod1 mutations. Ann Neurol,2007,61:427-434.
8 Gijselinck I, Sleegers K, Engelborghs S, et al. Neuronal inclusion protein tdp-43 has no primary genetic role in ftd and als. Neurobiol Aging,2007,
9 Gitcho MA, Baloh RH, Chakraverty S, et al. Tdp-43 a315t mutation in familial motor neuron disease. Ann Neurol,2008,63:535-538.
10 Rutherford NJ, Zhang YJ, Baker M, et al. Novel mutations in tardbp (tdp-43) in patients with familial amyotrophic lateral sclerosis. PLoS Genet,2008,4:e 1000193.
11 Van Deerlin VM, Leverenz JB, Bekris LM, et al. Tardbp mutations in amyotrophic lateral sclerosis with tdp-43 neuropathology:A genetic and histopathological analysis. Lancet Neurol,2008,7:409-416.
12 Winton MJ, Van Deerlin VM, Kwong LK, et al. A90v tdp-43 variant results in the aberrant localization of tdp-43 in vitro. FEBS Lett,2008,582:2252-2256.
13 Yokoseki A, Shiga A, Tan CF, et al. Tdp-43 mutation in familial amyotrophic lateral sclerosis. Ann Neurol,2008,63:538-542.
14 Rollinson S, Snowden JS, Neary D, et al. Tdp-43 gene analysis in frontotemporal lobar degeneration. Neurosci Lett,2007,419:1-4.
15 Sreedharan J, Blair IP, Tripathi VB, et al. Tdp-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science,2008,319:1668-1672.
16 Kabashi E, Valdmanis PN, Dion P, et al. Tardbp mutations in individuals with sporadic and familial amyotrophic lateral sclerosis. Nat Genet,2008,40:572-574.
17 Kuhnlein P, Sperfeld AD, Vanmassenhove B, et al. Two german kindreds with familial amyotrophic lateral sclerosis due to tardbp mutations. Arch Neurol,2008, 65:1185-1189.
18 Daoud H, Valdmanis PN, Kabashi E, et al. Contribution of tardbp mutations to sporadic amyotrophic lateral sclerosis. J Med Genet,2009,46:112-114.
19 Del Bo R, Ghezzi S, Corti S, et al. Tardbp (tdp-43) sequence analysis in patients with familial and sporadic als:Identification of two novel mutations. Eur J Neurol, 2009,
20 Corrado L, Ratti A, Gellera C, et al. High frequency of tardbp gene mutations in italian patients with amyotrophic lateral sclerosis. Hum Mutat,2009,30:688-694.
21 Lemmens R, Race V, Hersmus N, et al. Tdp-43 m311v mutation in familial amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry,2009,80:354-355.
22 Guerreiro RJ, Schymick JC, Crews C, et al. Tdp-43 is not a common cause of sporadic amyotrophic lateral sclerosis. PLoS ONE,2008,3:e2450.
23 Zoccolella S, Beghi E, Palagano G, et al. Signs and symptoms at diagnosis of amyotrophic lateral sclerosis:A population-based study in southern italy. Eur J Neurol, 2006,13:789-792.
24 Banks GT, Kuta A, Isaacs AM, et al. Tdp-43 is a culprit in human neurodegeneration, and not just an innocent bystander. Mamm Genome,2008, 19:299-305.
25 Vance C, Rogelj B, Hortobagyi T, et al. Mutations in fus, an rna processing protein, cause familial amyotrophic lateral sclerosis type 6. Science,2009,323:1208-1211.
26 Kwiatkowski TJ, Jr., Bosco DA, Leclerc AL, et al. Mutations in the fus/tls gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science,2009, 323:1205-1208.
2 Simpson CL, Al-Chalabi A. Amyotrophic lateral sclerosis as a complex genetic disease. Biochim Biophys Acta,2006,1762:973-985.
3 Eberle MA, Ng PC, Kuhn K, et al. Power to detect risk alleles using genome-wide tag snp panels. PLoS Genet,2007,3:1827-1837.
4 Dunckley T, Huentelman MJ, Craig DW, et al. Whole-genome analysis of sporadic amyotrophic lateral sclerosis. N Engl J Med,2007,357:775-788.
5 Schymick JC, Scholz SW, Fung HC, et al. Genome-wide genotyping in amyotrophic lateral sclerosis and neurologically normal controls:First stage analysis and public release of data. Lancet Neurol,2007,6:322-328.
6 van Es MA, Van Vught PW, Blauw HM, et al. Itpr2 as a susceptibility gene in sporadic amyotrophic lateral sclerosis:A genome-wide association study. Lancet Neurol, 2007,6:869-877.
7 van Es MA, van Vught PW, Blauw HM, et al. Genetic variation in dpp6 is associated with susceptibility to amyotrophic lateral sclerosis. Nat Genet,2008,40:29-31.
8 Cronin S, Berger S, Ding J, et al. A genome-wide association study of sporadic als in a homogenous irish population. Hum Mol Genet,2008,17:768-774.
9 Traynor BJ, Singleton A. Genome-wide association studies and als:Are we there yet? Lancet Neurol,2007,6:841-843.
10 Pusch W, Wurmbach JH, Thiele H, et al. Maldi-tof mass spectrometry-based snp genotyping. Pharmacogenomics,2002,3:537-548.
11 Mackenzie IR, Rademakers R. The role of transactive response DNA-binding protein-43 in amyotrophic lateral sclerosis and frontotemporal dementia. Curr Opin Neurol,2008,21:693-700.
12 Arai T, Hasegawa M, Akiyama H, et al. Tdp-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Biochem Biophys Res Commun,2006,351:602-611.
13 Neumann M, Sampathu DM, Kwong LK, et al. Ubiquitinated tdp-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science,2006, 314:130-133.
14 Gitcho MA, Baloh RH, Chakraverty S, et al. Tdp-43 a315t mutation in familial motor neuron disease. Ann Neurol,2008,63:535-538.
15 Rutherford NJ, Zhang YJ, Baker M, et al. Novel mutations in tardbp (tdp-43) in patients with familial amyotrophic lateral sclerosis. PLoS Genet,2008,4:e1000193.
16 Van Deerlin VM, Leverenz JB, Bekris LM, et al. Tardbp mutations in amyotrophic lateral sclerosis with tdp-43 neuropathology:A genetic and histopathological analysis. Lancet Neurol,2008,7:409-416.
17 Winton MJ, Van Deerlin VM, Kwong LK, et al. A90v tdp-43 variant results in the aberrant localization of tdp-43 in vitro. FEBS Lett,2008,582:2252-2256.
18 Yokoseki A, Shiga A, Tan CF, et al. Tdp-43 mutation in familial amyotrophic lateral sclerosis. Ann Neurol,2008,63:538-542.
19 Sreedharan J, Blair IP, Tripathi VB, et al. Tdp-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science,2008,319:1668-1672.
20 Kabashi E, Valdmanis PN, Dion P, et al. Tardbp mutations in individuals with sporadic and familial amyotrophic lateral sclerosis. Nat Genet,2008,40:572-574.
21 Kuhnlein P, Sperfeld AD, Vanmassenhove B, et al. Two german kindreds with familial amyotrophic lateral sclerosis due to tardbp mutations. Arch Neurol,2008, 65:1185-1189.
22 Daoud H, Valdmanis PN, Kabashi E, et al. Contribution of tardbp mutations to sporadic amyotrophic lateral sclerosis. J Med Genet,2009,46:112-114.
23 Del Bo R, Ghezzi S, Corti S, et al. Tardbp (tdp-43) sequence analysis in patients with familial and sporadic als:Identification of two novel mutations. Eur J Neurol,2009,
24 Corrado L, Ratti A, Gellera C, et al. High frequency of tardbp gene mutations in italian patients with amyotrophic lateral sclerosis. Hum Mutat,2009,30:688-694.
25 Lemmens R, Race V, Hersmus N, et al. Tdp-43 m311 v mutation in familial amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry,2009,80:354-355.
26 Reed GH, Kent JO, Wittwer CT. High-resolution DNA melting analysis for simple and efficient molecular diagnostics. Pharmacogenomics,2007,8:597-608.
27 Cronin, S. Tomik, B. Bradley, D. G, et al. Screening for replication of genome-wide SNP associations in sporadic ALS. Eur J Hum Genet,2008,17:213-218.
28 KIein,R J.Zeiss,C.Chew, E. Y., et al. Complement Factor H Polymorphism in Age-Related Macular Degeneration. Science,2005,308:385-389.
29 Hopitzan, A. A.Baines, A. J.Kordeli, E. Molecular evolution of ankyrin:gain of function in vertebrates by acquisition of an obscurin/titin-binding-related domain. Mol Biol Evol 2006,23:46-55.
30 Stabach, P. R. Devarajan, P. Stankewich, M. C. Ankyrin facilitates intracellular trafficking of alpha1-Na+-K+-ATPase in polarized cells. Am J Physiol Cell Physiol.2008, 295:C1202-14.
31 Guerreiro RJ, Schymick JC, Crews C, et al. Tdp-43 is not a common cause of sporadic amyotrophic lateral sclerosis. PLoS ONE,2008,3:e2450.
1 Miller RG, Mitchell JD, Lyon M, et al. Riluzole for amyotrophic lateral sclerosis (als)/motor neuron disease (mnd). Cochrane Database Syst Rev,2007:CD001447.
2 张莉红,李晓光,崔丽英.肌萎缩侧索硬化与超氧化物歧化酶1基因突变研究进展.中华神经科杂志,2007,40：65-67.
3 van Es MA, Van Vught PW, Blauw HM, et al. Itpr2 as a susceptibility gene in sporadic amyotrophic lateral sclerosis:a genome-wide association study. Lancet Neurol,2007,6: 869-877.
4 Simpson CL, Al-Chalabi A. Amyotrophic lateral sclerosis as a complex genetic disease. Biochim Biophys Acta,2006,1762:973-985.
5 The international hapmap project. Nature,2003,426:789-796.
6 Eberle MA, Ng PC, Kuhn K, et al. Power to detect risk alleles using genome-wide tag snp panels. PLoS Genet,2007,3:1827-1837.
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