title: The African-387 C>T TGFB1 variant is functional and associates with the ophthalmoplegic complication in juvenile myasthenia gravis.
abstract: Although extraocular muscles are commonly affected by myasthenia gravis (MG) at presentation, a treatment-resistant ophthalmoplegic complication of MG (OP-MG) occurs in younger patients with African-genetic ancestry. In MG, pathogenic antibodies activate complement-mediated muscle damage and this may be potentiated in some OP-MG cases because of relative deficiency of decay-accelerating factor/CD55. Extending this argument, we hypothesized that OP-MG individuals may harbor African-specific polymorphisms in key genes influencing extraocular muscle remodeling. We screened the regulatory region of the transforming growth factor beta-1 (TGFB1) gene encoding the cytokine pivotal in muscle healing responses. We show the frequency of an African-specific polymorphism TGFB1 c.-387 T (rs11466316) among South Africans with African-genetic ancestry is higher than 1000 Genomes African controls (17.2% vs 4.8%; P<1 × 10(-7)), and associates with juvenile OP-MG (28%; P=0.043). Further, TGFB1 -387 C>T is functional because it represses the TGFB1 promoter construct basal activity by fivefold, and OP-MG fibroblasts (-387 C/T or T/T) have lower basal TGFB1 mRNA transcripts compared with controls (-387 C/C)(P=0.001). Co-transfections with Sp1 show less responsiveness of the -387 T promoter compared with wild-type -387 C (P=0.015). Our findings suggest that population-specific alleles may lower TGFB1 expression, thereby influencing OP-MG susceptibility by inhibiting extraocular muscle CD55 upregulation and/or altered endplate remodeling.
authors.affiliation: Neurology Research Group, Division of Neurology, Department of Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: Melissa
authors.initials: M
authors.lastname: Nel
authors.affiliation: Neurology Research Group, Division of Neurology, Department of Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: Joy-Mari
authors.initials: JM
authors.lastname: Buys
authors.affiliation: Neurology Research Group, Division of Neurology, Department of Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: Robyn
authors.initials: R
authors.lastname: Rautenbach
authors.affiliation: Division of Haematology, Clinical Laboratory Sciences, University of Cape Town, Cape Town, South Africa.
authors.forename: Shaheen
authors.initials: S
authors.lastname: Mowla
authors.affiliation: Division of Cell Biology, Department of Human Biology, University of Cape Town, Cape Town, South Africa.
authors.forename: Sharon
authors.initials: S
authors.lastname: Prince
authors.affiliation: Neurology Research Group, Division of Neurology, Department of Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: Jeannine M
authors.initials: JM
authors.lastname: Heckmann
mesh_terms: D000293:Adolescent; D000328:Adult; D044383:Black People; D018958:CD55 Antigens / Q000235:genetics; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D056726:Genetic Association Studies; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008297:Male; D009157:Myasthenia Gravis / Q000150:complications / Q000235:genetics* / Q000473:pathology; D009886:Ophthalmoplegia / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics; D053773:Transforming Growth Factor beta1 / Q000235:genetics*
chemical_list: D018958:CD55 Antigens; D012333:RNA, Messenger; C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1