Myasthenia Gravis is an autoimmune neuromuscular disorder in which antibodies are produced against several muscle antigens. Immunological evidence indicates that the muscle antigens are also expressed in thymus. In the present proposal, we plan to 1) identify not yet characterized 'non-cholinergic"""""""" antigens in MG; 2) assess their pathological importance; 3) investigate transcriptional and genetic characteristics that may lead to deregulation in the expression of muscle and thymic peptides (and proteins) that become antigens in MG and 4) develop MG familial pedigrees for future linkage analysis. The studies will be conducted employing available cDNA clones and new cDNA clones selected from expression cDNA libraries: 1) Non- cholinergic cDNA clones are selected by screening expression cDNA libraries with MG sera known to react with different muscle antigens; 2) cDNA clones that code for the four subunits of the mouse AcChR will be employed to isolate their correspondent human counterparts. Identification of non-cholinergic antigens will be carried out through cDNA sequencing of the corresponding cDNA clones and immunological identification of the native protein by antibodies raised against the corresponding recombinant peptide. To assess the pathological significance of a peptide coded for a given cDNA clone, recombinant peptides will be employed in tests devised to determine antibody titers of individual MG sera. Titers will then be correlated with disease activity. To investigate transcriptional and genetic characteristics that may account for mechanisms leading to an autoimmune attack (i.e. antigenic deregulation), the selected (cholinergic and non- cholinergic) cDNA clones will be employed to analyze muscle and thymic transcripts from normal and MG tissues (Northern blot analysis) and for the study of the genomic characteristics (Southern blot analysis) of normal and MG tissues. Fine transcriptional analysis, employing nuclease protection assays, will be conducted with full length cDNA probes. cDNA clones will also be employed for the selection of genomic DNA clones from a human genomic library. These genomic clones will be incorporated as tools in the genomic DNA analysis of MG patients and control. Establishment of MG familial pedigrees for future linkage analysis will be carried out (Core A).

Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Duke University
Department
Type
DUNS #
071723621
City
Durham
State
NC
Country
United States
Zip Code
27705
Griswold, Anthony J; Van Booven, Derek; Cuccaro, Michael L et al. (2018) Identification of rare noncoding sequence variants in gamma-aminobutyric acid A receptor, alpha 4 subunit in autism spectrum disorder. Neurogenetics 19:17-26
Zhu, Zuobin; Lu, Xitong; Yuan, Dejian et al. (2017) Close genetic relationships between a spousal pair with autism-affected children and high minor allele content in cases in autism-associated SNPs. Genomics 109:9-15
Correia, Catarina; Oliveira, Guiomar; Vicente, Astrid M (2014) Protein interaction networks reveal novel autism risk genes within GWAS statistical noise. PLoS One 9:e112399
Gaugler, Trent; Klei, Lambertus; Sanders, Stephan J et al. (2014) Most genetic risk for autism resides with common variation. Nat Genet 46:881-5
Hadjixenofontos, Athena; Schmidt, Michael A; Whitehead, Patrice L et al. (2013) Evaluating mitochondrial DNA variation in autism spectrum disorders. Ann Hum Genet 77:9-21
Anney, Richard; Klei, Lambertus; Pinto, Dalila et al. (2012) Individual common variants exert weak effects on the risk for autism spectrum disorders. Hum Mol Genet 21:4781-92
Cukier, Holly N; Lee, Joycelyn M; Ma, Deqiong et al. (2012) The expanding role of MBD genes in autism: identification of a MECP2 duplication and novel alterations in MBD5, MBD6, and SETDB1. Autism Res 5:385-97
Griswold, Anthony J; Ma, Deqiong; Cukier, Holly N et al. (2012) Evaluation of copy number variations reveals novel candidate genes in autism spectrum disorder-associated pathways. Hum Mol Genet 21:3513-23
Casey, Jillian P; Magalhaes, Tiago; Conroy, Judith M et al. (2012) A novel approach of homozygous haplotype sharing identifies candidate genes in autism spectrum disorder. Hum Genet 131:565-79
Cuccaro, Michael L; Tuchman, Roberto F; Hamilton, Kara L et al. (2012) Exploring the relationship between autism spectrum disorder and epilepsy using latent class cluster analysis. J Autism Dev Disord 42:1630-41

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