title: [Studies on the genetic pathogenesis of myasthenia gravis caused by CTLA-4 gene polymorphism].
abstract: OBJECTIVE
  To study the genetic pathogenesis of myasthenia gravis (MG) caused by cytotoxic T lymphocyte associated antigen-4 (CTLA-4) gene polymorphisms and regulation function of transcription factor.
  
  
  METHODS
  ELISA assay was used to determine the expression level of serum sCTLA-4 in MG. Four single nucleotide polymorphisms (SNPs) of CTLA-4 at exon 1 +49, promoter -318, -1661, -1772 were analyzed by restriction fragment length polymorphism (RFLP). Transcription factor nuclear factor 1(NF-1) and c/EBPbeta binding site were confirmed by chromatin immunoprecipitation(CHIP) assay.
  
  
  RESULTS
  It was found that the frequencies of the GG+49 genotype and G+49 allele are higher in MG patients with thymoma than those in patients of thymic hyperplasia and normal thymus subgroups. T/C-318 is not correlated with MG. The frequency of CT-1772 genotype is significantly higher in MG patients, especially in MG patients with thymoma, when compared with that in healthy controls. Meanwhile, the frequency of the G-1661 allele and GG-1661 genotype is lower in MG patients. Linkage disequilibrium (LD) between each SNPs in promoter -1772, -1661, -318 and coding sequence 1 (CDS 1) +49 is apparent. sCTLA-4 levels in patients' sera are correlated with the haplotype and genotype. T/C-1772 and A/G-1661 SNPs change the sequence of transcription factor NF-1 and c/EBPbeta binding sites. DNA variants lose site-specific binding activity of transcription factor regulated by lectin ConA and PHA.
  
  
  CONCLUSIONS
  There are strong positive linkages among four SNPs. C/T-1772 and A/G-1661 polymorphisms can result in inefficient transcription of CTLA-4 gene. T>C-1772 mutation also affects gene splicing. These SNPs may constitute a factor of susceptibility to disease.
authors.affiliation: Institute of Basic Medical Research, Shandong Academy of Medical Sciences, Jinan, Shandong, 250062 P. R. China.
authors.forename: Hai-ting
authors.initials: HT
authors.lastname: Mao
authors.forename: Xiong-biao
authors.initials: XB
authors.lastname: Wang
authors.forename: Ling
authors.initials: L
authors.lastname: Zhang
authors.forename: Hong-tao
authors.initials: HT
authors.lastname: Gu
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000097:blood / Q000235:genetics*; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics; D060908:CTLA-4 Antigen; D005091:Exons; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009157:Myasthenia Gravis / Q000235:genetics* / Q000276:immunology; D051839:NFI Transcription Factors; D017354:Point Mutation; D012150:Polymorphism, Restriction Fragment Length; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D013945:Thymoma / Q000235:genetics; D013952:Thymus Hyperplasia / Q000235:genetics; D013953:Thymus Neoplasms / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics
chemical_list: D015703:Antigens, CD; D000943:Antigens, Differentiation; D022782:CCAAT-Enhancer-Binding Protein-beta; D022762:CCAAT-Enhancer-Binding Proteins; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D051839:NFI Transcription Factors; D014157:Transcription Factors