The gene at stake
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Establishing the mode of inheritance of a disease is insufficient to get a good understanding of a condition. Finding the genes involved in a pathology and the molecular pathways at stake is crucial to potentially develop treatments. And even before envisaging treatments, it is still very useful in confirming diagnosis in people presenting clinical signs of vEDS through genetic tests.
The genetic etiology of vEDS was discovered in the 1960s following studies of several clinical cases.
vEDS was found to be due to mutations in the COL3A1 gene at locus 2q32.2. This gene actually encodes for the alpha 1 chain of collagen III, which forms part of artery walls, skin, and capsules surrounding organs such as the intestines and the uterus. (Wikipedia, 2018 ; Rafique, 2008 ; Wikipedia, 2018 ; Orphanet, 2018). The impact of COL3A1 mutations in developing the symptoms of vEDS has also been shown in mice models harboring mutations in their COL3A1 gene (Mao and Bristow, 2001).
What makes vEDS that large in its clinical spectrum is that collagen III encoded by COL3A1 gene actually acts at many different locations in the body. Defects in this gene can turn to be very harmful, and cause blood vessels or internal organs to split open, while also increasing skin elasticity (NHS, 2016).
Two mutations associated with vEDS have also been found at locus 9q34.3 on the COL5A1 gene. This gene encodes for the alpha 1 chain of collagen V, which contributes to the bone matrix, and the interstitial matrix of muscles, liver, lungs and placenta (Leeming and Karsdal, 2016). Heterozygous mutations on COL5A1 gene are more known to be associated with classic EDS though. One of the two cases reported to have vEDS actually shows overlapping features of both vascular and classical EDS (Dalgleish, 2014).
So far, no other COL5A1 variant has been reported to be correlated with vEDS worldwide. COL3A1 gene is definitely considered the gene involved in developing vEDS.
Note that not all of the EDS types are characterized by mutations in a gene encoding collagen, but possibly in other genes encoding proteins interacting with collagen (Collins, 2014).
Finally, it must be said that even before COL3A1 variants were found to give rise to vEDS, there were some strong suggestions that collagen should play a role in giving rise to the symptoms observed in the patients. At first, elastin was considered of potential interest as one of the symptoms of the patients is skin elasticity. But the study conducted by Jansen in 1955 showed that there was no defect in elastin structure while an abnormal structure of collagen in EDS affected people. Thus, both molecular and genetic studies have contributed to establish the etiology of vEDS (Jansen, 1955).
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References :
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Rafique M. (2008) Connective Tissues Fibers and Ground Substance. Available at https://slideplayer.com/slide/6075827/ (Accessed : 18 November 2018)
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Wikipedia (2018) Reticular fiber. Available at https://en.wikipedia.org/w/index.php?title=Reticular_fiber&oldid=821571115 (Accessed : 18 November 2018)
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Wikipedia (2018) Collagen. Available at https://en.wikipedia.org/w/index.php?title=Collagen&oldid=868519397 (Accessed : 18 November 2018)
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Orphanet (2018). COL3A1 - collagen type III alpha 1 chain. Available at https://www.orpha.net/consor/cgi-bin/Disease_Genes.php?lng=EN&data_id=15770&MISSING%20CONTENT=collagen-type-III-alpha-1-chain&search=Disease_Genes_Simple&title=collagen%20type%20III%20alpha%201%20chain (Accessed : 18 November 2018)
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Mao, J.R. Bristow, J. (2001), ‘The Ehlers-Danlos syndrome: on beyond collagens’, J Clin Invest. 107(9): 1063–1069.
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NHS (2016). Ehlers-Danlos syndromes. Available at https://www.nhs.uk/conditions/ehlers-danlos-syndromes/ (Accessed : 18 November 2018)
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Leeming D.J. Karsdal M.A. (2016) Biochemistry of Collagens, Laminins and Elastin : Structure, Function and Biomarkers. Academic Press.
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Dalgleish R. (2014). Collagen, type V, alpha 1 (COL5A1). Available at https://eds.gene.le.ac.uk/variants.php?select_db=COL5A1&action=search_all&order=pathogenic_%2CASC&hide_col=&show_col=&limit=100&search_pathogenic_=&search_Variant%2FExon=&search_Variant%2FDNA=&search_Variant%2FDbSNP=&search_Variant%2FType=&search_Variant%2Fmutation_type=&search_Variant%2FProtein=&search_Variant%2FRNA=&search_Variant%2FRestriction_site=&search_Variant%2FFrequency=&search_Variant%2FDBID=&search_Patient%2FPatient_ID=&search_Patient%2FPhenotype%2FDisease=Vascular+EDS&search_Patient%2FReference=&search_Patient%2FDetection%2FTemplate=&search_Patient%2FDetection%2FTechnique=&search_Patient%2FRemarks=&search_Patient%2FOrigin%2FEthnic= (Accessed : 18 November 2018)
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Collins H. (2014) If you can’t connect the issues, think connective tissues. Available at https://www.ehlers-danlos.com/2014-annual-conference-files/Heidi%20Collins.pdf (Accessed : 18 November 2018)
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Jansen, L.H. (1955), ‘The Structure of the Connective Tissue, an Explanation of the Symptoms of the Ehlers-Danlos Syndrome’, Dermatologica, 110, 108​
