Involvement of human muscle acetylcholine receptor alpha-subunit gene (CHRNA) in susceptibility to myasthenia gravis.

Abstract

The muscle acetylcholine receptor is the major target of the autoimmune response in generalized myasthenia gravis. To investigate the role of the gene encoding the a subunit of the receptor (CHRNA), two stable polymorphic d[(GT)-(CA)]dinucleotide repeats, designated HB and BB, were characterized within the first intron of CHRNA. The HB*14 allele conferred a relative risk for myasthenia gravis of 2.5 in 81 unrelated patients compared with 100 control subjects. Very sinficantly, family analysis based on haplotype segregation data indicated that parental haplotypes associated with HB*14 always segregated to the child with myasthenia gravis (P < 0.0002 for the comparison with the transmission of haplotypes not bearing HB*14), whereas their transmission to unaffected siblings was equilibrated. Myasthenia gravis patients also showed a high frequency of microsatellite variants unseen in controls. These findings implicate the CHRNA in susceptibility to myasthenia gravis.

Epistasis between DSG1 and HLA class II genes in pemphigus foliaceus

“…Among these, genes encoding autoantigens can contribute to disease susceptibility, as demonstrated by the association of the acetylcholine receptor alpha-subunit gene (CHRNA) polymorphism with myasthenia gravis. 3 Furthermore, in this organ-specific autoimmune disease, a three-gene model involving HLA class II DQA*0101, DRB*03 genes and CHRNA has been proposed that supports the concept of epistasis. 4 Pemphigus is a group of rare and severe cutaneous organ-specific autoimmune diseases, characterized by the production of autoantibodies directed against desmosomal adhesion molecules expressed by keratinocytes 5 and responsible for the formation of intraepidermal blisters.…”

“…The two loci studied were MHC class II genes and DSG1 which encodes the target autoantigen of the pathogenic antibodies produced during the course of PF. The rationale to study the role and the interaction of these two genetic elements was: first, MHC class II genes have been shown to play a pivotal role in most autoimmune diseases and also to be associated with the endemic 13,14 and the sporadic forms [15][16][17] of PF; and, second, it is well established that autoantigens participate in the triggering of the B-and T-cell autoimmune responses in autoimmune diseases, and that polymorphism of the corresponding autoantigen can contribute to the autoimmune trait susceptibility as shown for the CHRNA gene in myasthenia gravis 3 and the insulin gene in IDDM. 22 In this association analysis involving the largest series of PF patients so far studied and 84 healthy controls, HLA-DRB1*0102, DRB1*0402 and 0406 and DRB1*1404 were shown to be significantly associated with PF.…”

“…This observation of epistatic interaction is reminiscent of results obtained in two other organ-specific autoimmune diseases, in which the interactive effect of two different loci was demonstrated: IDDM with the insulin gene and the HLA region, 24 and myasthenia gravis with CHRNA and two different HLA loci. 3,4 How HLA class II genes and the C/C(809) genotype interact to mediate PF susceptibility might be explained by the fact that MHC class II molecules and autoantigens intervene in the biological pathway leading to the autoimmune processes and tolerance breakage of autoreactive lymphocytes, since MHC gene products present antigens to immune T cells. 25 The C/T polymorphism at position 809 is a silent mutation and therefore, does not directly modify a putative T-cell epitope on the corresponding region of DSG1.…”

Genetic control of autoantibody expression in autoimmune myasthenia gravis: role of the self-antigen and of HLA-linked loci

“…We notably investigated the CHRNA1 gene, which encodes the a-subunit, the target of most autoantibodies. 4 Using a microsatellite located in its first intron, we previously showed an association with MG of an allele of this microsatellite, designated HB*14, 18 a finding that was reproduced in different populations. 19 Remarkably, a synergistic association was also characterized between HB*14 and two HLA-linked gene alleles.…”

“…Their correlations were described previously. 13 Microsatellite and HLA genotyping Genotyping of the TNFD and HB microsatellites was conducted as before, 18,41 except that one of the oligonucleotide primers that was used for amplification was tagged with a fluorescent label. Amplification products were migrated on an ABI 373XL automated sequencer (Applied Biosystems).…”