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MYASTHENIA GRAVIS WITH THYMUS HYPERPLASIA

MYASTHENIA GRAVIS WITH THYMUS HYPERPLASIA

Alternative titles; symbolsMYAS1Cytogenetic location: 6p21.3 Genomic coordinates (GRCh38): 6:33,500,000-36,600,000Myasthenia gravis (MG; see 254200) is an au...

Alternative titles; symbols

  • MYAS1

Cytogenetic location: 6p21.3 Genomic coordinates (GRCh38): 6:33,500,000-36,600,000

Myasthenia gravis (MG; see 254200) is an autoimmune disease of the neuromuscular junction that is often found in association with other autoimmune disorders. Association studies using case-control designs, i.e., comparisons of unrelated patients and control subjects, had demonstrated an increased frequency of the extended HLA haplotype A1-B8-DR3 (8.1) in Caucasian MG patients with thymus hyperplasia, in women, and in patients with an early onset of disease (Fritze et al., 1974; Vieira et al., 1993; Machens et al., 1999). To reevaluate the association of HLA with MG in 656 patients with generalized disease, and to test linkage of HLA to MG with thymus hyperplasia, Giraud et al. (2001) studied transmission of parental alleles to MG offspring with thymus hyperplasia in simplex (single-case) families using the transmission/disequilibrium test (TDT) as a test of linkage. Their results indicated linkage of HLA to MG with thymus hyperplasia, defining a locus on chromosome 6p21.3 that they designated MYAS1. They found that DR3 and DR7, or closely linked genes, had opposing effects on MG phenotypes. MG with thymus hyperplasia was positively associated with DR3 and negatively associated with DR7, based on both case-control comparisons and TDT. Conversely, patients who lacked thymus anomalies but expressed antibodies against titin (188840) had an increase of DR7 and a decrease of DR3.

The 8.1 haplotype of the major histocompatibility complex (MHC) associates not only with the HLA DR3, B8, and A1 antigens but also alleles of many other HLA loci and extends over 3 Mb stably across generations in Caucasians. This haplotype is associated with highly prevalent autoimmune diseases (Price et al., 1999). Vandiedonck et al. (2004) localized the MYAS1 gene to a 1.2-Mb genome segment by reconstructing haplotypes and assessing their transmission in 73 simplex families. This segment encompasses the class III and proximal class I regions, between the BAT3 (142590) and C3-2-11 markers, thereby unambiguously excluding the class II loci. In addition, a case-control study revealed a very strong association with a core haplotype in this same region following an additive model; odds ratio was 6.5 for 1 copy and 42 for 2 copies of the core haplotype. Vandiedonck et al. (2004) showed that this region is associated with a marked increase in serum titers of antiacetylcholine receptor autoantibodies. This effect was suppressed by a second locus in cis on the 8.1 haplotype and located toward the class II region. Vandiedonck et al. (2004) concluded that these data demonstrated the highly significant but complex effects of the 8.1 haplotype on the phenotype of myasthenia gravis patients.

Tags: 6p21.3