EquiSeq plaatste gisteren dit over de erfelijkheid van PSSM2. Voor de liefhebber ook met links naar wetenschappelijk onderzoek. Let op: dit gaat niét over de validiteit van de tests maar puur over of pssm2 erfelijk is of niet. In het Engels:
EquiSeq schreef:We were asked on the PSSM Forum to provide a reasoned argument for the hypothesis that the disease state PSSM2 results from the inheritance of genetic variants. This was our response.
Here is a brief reasoned argument for the hypothesis that the disease state PSSM2, including the subtype MFM, results from the inheritance of pathogenic variants.
Horses with PSSM1 have an inherited disorder in the gene encoding glycogen synthase. The GYS1-R309H genetic variant is associated with the disease state PSSM1 by GWAS (1) and results in a constitutively activated glycogen synthase (2).
There is a disease state called PSSM2 (including the subtype MFM) in which horses display symptoms of exercise intolerance and show abnormalities of muscle observable by muscle biopsy. These abnormalities include the pooling of glycogen granules of normal size in areas of myofibrillar disorganization, giving the false appearance of a glycogen storage disorder (3, 4).
The PSSM2 subtype called MFM is diagnosed by identifying ectopic aggregates of desmin-positive material outside of the Z disc. This is assessed in the light microscope by immunological staining with anti-desmin antibodies. Electron microscopy of muscle samples from affected horses shows breaks in the Z disc and Z disc streaming (4). These features are seen in the human Myofibrillar Myopathies, which are a subtype of Limb-Girdle Muscular Dystrophy (5,6).
In humans, inherited defects in dozens of different independently inherited genes cause Limb-Girdle Muscular Dystrophy and Myofibrillar Myopathy. There are human cases that cannot be assigned to any of the known causative genes. There is ample evidence that these cases are inherited, and the search for additional genetic defects in other genes is an active area of investigation.
It is a fundamental premise of genomics and molecular genetics that mammals share a common set of genes derived by descent from a common ancestor, and that investigations of inherited conditions in one mammal are of value in understanding similar conditions in other mammals. The evidence that this is a productive strategy for investigation is overwhelming. Billions of dollars have be invested successfully in biomedical research based on this premise.
There is no evidence that human Myofibrillar Myopathy or Limb-Girdle Muscular Dystrophy results from any cause besides the inheritance of genetic variants. These conditions do not result from infectious agents, dietary deficiency of any nutrient, or other environmental effects.
Therefore, the working hypothesis on equine myopathies is that they result from the inheritance of genetic defects, as they do in humans.
1. McCue ME, Valberg SJ, Miller MB, Wade C, DiMauro S, Akman HO, Mickelson JR. Glycogen synthase (GYS1) mutation causes a novel skeletal muscle glycogenosis. Genomics. 2008 May;91(5):458-466.
2. Maile CA, Hingst JR, Mahalingan KK, O'Reilly AO, Cleasby ME, Mickelson JR, McCue ME, Anderson SM, Hurley TD, Wojtaszewski JFP, Piercy RJ. A highly prevalent equine glycogen storage disease is explained by constitutive activation of a mutant glycogen synthase. Biochim Biophys Acta Gen Subj. 2017 Jan;1861(1 Pt A):3388-3398.
3. McCue ME, Armién AG, Lucio M, Mickelson JR, Valberg SJ. Comparative skeletal muscle histopathologic and ultrastructural features in two forms of polysaccharide storage myopathy in horses. Vet Pathol. 2009 Nov;46(6):1281-1291.
4. Valberg SJ, McKenzie EC, Eyrich LV, Shivers J, Barnes NE, Finno CJ. Suspected myofibrillar myopathy in Arabian horses with a history of exertional rhabdomyolysis. Equine Vet J. 2016 Sep;48(5):548-556.
5. Palmio J, Udd B. Myofibrillar and distal myopathies. Rev Neurol (Paris). 2016 Oct;172(10):587-593.
6. Taghizadeh E, Rezaee M, Barreto GE, Sahebkar A. Prevalence, pathological mechanisms, and genetic basis of limb-girdle muscular dystrophies: A review. J Cell Physiol. 2018 Dec 7. doi: 10.1002/jcp.27907.