Abstract
So far, mutations in the human COL3A1 gene have been associated with the predominantly inherited Ehlers–Danlos syndrome (EDS), vascular type. Genotype–phenotype correlation perspectives collapsed, as haploinsufficiency, which was long suggested to confer a milder or unrecognized phenotype, was reported in four patients with a phenotype similar to that of vascular EDS. Here, we study a case of recessive EDS in a young consanguineous girl of healthy parents. She fulfilled the vascular EDS criteria for laboratory testing. Total sequencing of COL3A1 cDNA identified a homozygous nucleotide duplication (c.479dupT) resulting in a premature termination codon (p.Lys161GlnfsX45). Studies in genomic DNA showed that this mutation was inherited from each parent. The expression analysis (RT-PCR, quantitative-PCR, immunohistochemistry, WB) showed strong mRNA decay and an absence of type III collagen in the proband. The expected COL3A1 haploinsufficiency in her healthy ascendants did not lead to the manifestations of vascular EDS. This case provides evidence of a stochastic effect of COL3A1 haploinsufficiency in humans, which could be explained by the relation between nonsense-mediated mRNA decay efficiency and the resulting dominant-negative effect depending on the position of the mutation and/or modifying factors. It opens up new perspectives for the understanding of COL3A1 genotype–phenotype correlations, which is required while considering targeted therapy.
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Acknowledgements
We gratefully acknowledge S Auvin, B Catteau, S Coopman, JM Cuisset and R Sfeir for referring the patient and for providing follow-up information, C Baudoin, N Pallares-Ruiz, C Rene and M Taulan for their technical advice and support and N Hornez for helping in preparing the paper. We also thank the clinical research team of the CHU of Montpellier, notably J Dinet and S Plagnol, for their support. A Plancke and part of this work were funded by the ‘Programme de Soutien aux Techniques Innovantes Coûteuses 2006’ from the French Ministry of Health. We are also especially grateful to X Jeunemaitre for his helpful comments.
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Supplementary Information accompanies the paper on European Journal of Human Genetics website (http://www.nature.com/ejhg)
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Plancke, A., Holder-Espinasse, M., Rigau, V. et al. Homozygosity for a null allele of COL3A1 results in recessive Ehlers–Danlos syndrome. Eur J Hum Genet 17, 1411–1416 (2009). https://doi.org/10.1038/ejhg.2009.76
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DOI: https://doi.org/10.1038/ejhg.2009.76
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