CIGMR has an ongoing research programme to identify disease susceptibility genes in myasthenia gravis.
Myasthenia gravis (MG) is a prototypic autoantibody-mediated immune disorder, with a complex genetic basis. It is uncommon, with a prevalence of 1-2 cases per 10,000. The disorder is characterized by an abnormal immune response to the junction that connects nerves to skeletal muscles. This impairs the ability of the nerves to cause muscle contraction, leading to painless intermittent and chronic muscle weakness. The muscle weakness is mediated by autoantibodies against the muscle acetylcholine receptor in >80% of cases. The weakness typically affects movements of the eyes, face, throat, swallowing, speech and breathing. Eye movements are very often affected first: if that remains the only sign for ≥2 years, it is called ocular MG. More often, the weakness evolves gradually to affect other muscle groups.
Diagnosis of MG is very variable, both between and within patients. Due to the muscle fatigue, patients' weakness is often worse in the evenings, and easier to miss in the mornings, so diagnosis may be delayed. Its onset may be hard to date, and is frequently worsened by stress or infections. Diagnosis relies on electro-myography, and detection of autoantibodies against the acetylcholine receptor or muscle-specific kinase. Depletion of these antibodies is an effective therapy.
In Caucasians, patients with early-onset MG (before age 45) form a particularly well defined subgroup, with a 4:1 female bias and characteristic lymph node-like infiltrates in the thymic medulla. Recently, late-onset MG patients have been found to be more abundant than previously recognised. About 30% of all patients with epithelial tumours of the thymus (thymoma) develop MG with autoantibodies against the acetylcholine receptor. Thymectomy may increase the chances of remission in early-onset MG but not thymoma patients. Despite the prevalence, there are fewer clues to the causes of late-onset and ocular MG than in early-onset MG and thymoma patients.
Aims of our research
To identify genetic variants increasing risk of myasthenia gravis, in order to deepen understanding and lead to the development of new diagnostic and therapeutic approaches to this uncommon disorder.
Current research projects
Previous research has shown that, as in many other autoantibody-mediated immune diseases, early-onset MG is strongly associated with the intracellular phosphatase PTPN22 gene. Early-onset MG has also been shown to be associated with the common ancestral "8.1" haplotype of the histocompatibility leukocyte antigen (HLA) region. However, pinpointing the exact signal underlying this association has proved difficult.
In part due to the rarity of MG, comprehensive genetic analyses have been challenging to organize and have not yet been reported. As part of a large international collaboration, The Myasthenia Gravis Genetics Consortium (MGGC), we have recently carried out the first study of the whole human genome (a genomewide association study) to identify genetic variants that confer risk to early-onset Myasthenia Gravis. This study was carried out on a large sample of Northern European early-onset MG patients.
The results of this study were of significant interest in several respects. We identified several new genes involved in immune regulation that confer risk for Myasthenia Gravis. In addition to the expected association with PTPN22, we identified an association with the TNIP1 gene locus. This association has a relatively strong effect compared to most other genes that have been associated with autoimmunity, and we were able to identify an amino acid changing variant as the likely cause of early-onset MG. By using state of the art methodology and analyses, we were able also to narrow down the specific genes in the major histocompatibility complex region on chromosome 6 which are involved in this disorder.
This study was the first comprehensive analysis of Myasthenia Gravis to be reported. This supports the close genetic relationship of Myasthenia Gravis with other more common autoimmune disorders, provides an initial assessment of the genes involved in disease risk, and may open the way to deeper understanding and the development of new diagnostic and therapeutic approaches for this uncommon disorder.
Further studies of late-onset MG and thymoma MG are in progress.
People and collaborators
This research is being carried out in collaboration with Dr Jon Sussman and colleagues (Department of Neurology, Greater Manchester Neuroscience Centre, Salford Royal Foundation NHS Trust), and Prof Nick Willcox (Department of Clinical Neurology, Weatherall Institute for Molecular Medicine, University of Oxford, UK).
This research is part of an international collaboration, the Myasthenia Gravis Genetics Consortium (MGGC), including the following key collaborators: Peter Gregersen (Feinstein Institute for Medical Research, New York, US), Michael Seldin (University of California, Davis, US), Lennart Hammarstrom (Karolinska University Hospital, Stockholm, Sweden), Hanne Harbo (Oslo University Hospital and University of Oslo, Norway), Henri-Jean Garchon (Inserm, Paris, France), Jan Verschuuren & Maarten Titulaer (University Medical Center, Leiden, The Netherlands), Alexander Marx & Philipp Strobel (University of Heidelberg, Mannheim, Germany), Bjorn Tackenberg (University of Marburg, Germany), Arthur Melms (Tubingen University Medical Center, Tubingen, Germany).
Risk for myasthenia gravis maps to a (151) Pro→Ala change in TNIP1 and to human leukocyte antigen-B*08. Gregersen PK, Kosoy R, Lee AT, Lamb J, Sussman J, McKee D, Simpfendorfer KR, Pirskanen-Matell R, Piehl F, Pan-Hammarstrom Q, Verschuuren JJ, Titulaer MJ, Niks EH, Marx A, Strobel P, Tackenberg B, Putz M, Maniaol A, Elsais A, Tallaksen C, Harbo HF, Lie BA, Raychaudhuri S, de Bakker PI, Melms A, Garchon HJ, Willcox N, Hammarstrom L, Seldin MF. Ann Neurol. 2012 Dec;72(6):927-35.
MGGC research is supported by grants from the National Institutes of Health, the Swedish Research Council, the UK Medical Research Council, the Norwegian Health Authorities South East, the Prinses Beatrix Fonds, The Netherlands, and the Myasthenia Gravis Association, UK.