title: Homozygosity for a null allele of COL3A1 results in recessive Ehlers-Danlos syndrome.
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.
authors.affiliation: CHU Montpellier, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Plancke
authors.forename: Muriel
authors.initials: M
authors.lastname: Holder-Espinasse
authors.forename: Valérie
authors.initials: V
authors.lastname: Rigau
authors.forename: Sylvie
authors.initials: S
authors.lastname: Manouvrier
authors.forename: Mireille
authors.initials: M
authors.lastname: Claustres
authors.forename: Philippe
authors.initials: P
authors.lastname: Khau Van Kien
mesh_terms: D000483:Alleles; D002648:Child; D024061:Collagen Type III / Q000235:genetics*; D003241:Consanguinity; D004535:Ehlers-Danlos Syndrome / Q000235:genetics*; D005260:Female; D020440:Gene Duplication; D005808:Genes, Recessive; D006239:Haplotypes; D006720:Homozygote; D006801:Humans; D009154:Mutation; D010375:Pedigree
chemical_list: D024061:Collagen Type III