Diagnosis of vascular Ehlers-Danlos syndrome in Italy: Clinical findings and novel COL3A1 mutations

Drera, Bruno; Zoppi, Nicoletta; Ritelli, Marco; Barlati, Sergio; Colombi, Marina; Tadini, Gianluca; Venturini, Marina; Calzavara‐Pinton, Piergiacomo; Wischmeijer, Anita; Nicolazzi, Maria Anna; Musumeci, Alfredo; Penco, Silvana; Buscemi, Loredana; Crivelli, Sara; Danesino, Cesare; Clementi, Maurizio; Viglio, Simona; Valli, Maurizia

doi:10.1016/j.jdermsci.2011.09.002

Cited by 14 publications

(15 citation statements)

References 9 publications

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“…vEDS patients were positive for the criteria of the Villefranche nosology [ 2 ] and the 2017 revised nosology [ 3 ]. In particular, the three vEDS patients included in this study were previously characterized for three different structural mutations in COL3A1 [ 18 ]. vEDS patient 1 (P1) was heterozygous for the c.709G>A transition (p.Gly237Arg); patient 2 (P2) carried the c.951+6T>C splice site mutation that causes in-frame skipping of exon 14; patient 3 (P3) harbored the c.1835G>A missense variant (p.Gly612Asp).…”

Section: Patients Materials and Methodsmentioning

confidence: 99%

Transcriptome analysis of skin fibroblasts with dominant negative COL3A1 mutations provides molecular insights into the etiopathology of vascular Ehlers-Danlos syndrome

et al. 2018

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Vascular Ehlers-Danlos syndrome (vEDS) is a dominantly inherited connective tissue disorder caused by mutations in the COL3A1 gene that encodes type III collagen (COLLIII), which is the major expressed collagen in blood vessels and hollow organs. The majority of disease-causing variants in COL3A1 are glycine substitutions and in-frame splice mutations in the triple helix domain that through a dominant negative effect are associated with the severe clinical spectrum potentially lethal of vEDS, characterized by fragility of soft connective tissues with arterial and organ ruptures.To shed lights into molecular mechanisms underlying vEDS, we performed gene expression profiling in cultured skin fibroblasts from three patients with different structural COL3A1 mutations. Transcriptome analysis revealed significant changes in the expression levels of several genes involved in maintenance of cell redox and endoplasmic reticulum (ER) homeostasis, COLLs folding and extracellular matrix (ECM) organization, formation of the proteasome complex, and cell cycle regulation. Protein analyses showed that aberrant COLLIII expression is associated with the disassembly of many structural ECM constituents, such as fibrillins, EMILINs, and elastin, as well as with the reduction of the proteoglycans perlecan, decorin, and versican, all playing an important role in the vascular system. Furthermore, the altered distribution of the ER marker protein disulfide isomerase PDI and the strong reduction of the COLLs-modifying enzyme FKBP22 are consistent with the disturbance of ER-related homeostasis and COLLs biosynthesis and post-translational modifications, indicated by microarray analysis. Our findings add new insights into the pathophysiology of this severe vascular disorder, since they provide a picture of the gene expression changes in vEDS skin fibroblasts and highlight that dominant negative mutations in COL3A1 also affect post-translational modifications and deposition into the ECM of several structural proteins crucial to the integrity of soft connective tissues.

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Section: Patients Materials and Methodsmentioning

confidence: 99%

Transcriptome analysis of skin fibroblasts with dominant negative COL3A1 mutations provides molecular insights into the etiopathology of vascular Ehlers-Danlos syndrome

et al. 2018

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“…In JHS/EDS‐HT aortic dissections are extremely rare, and aortic root ectasia is observed with an overall incidence of approximatively 12% without an increased risk of dissection [Atzinger et al, ]. In vEDS visceral rupture (i.e., bowel, lungs, liver, spleen, uterus during pregnancy, heart) may also occur for internal organs fragility [Drera et al, ; Murray et al, ]; in JHS/EDS‐HT internal organs rupture is not reported, whereas visceroptosis due to ligaments hypoplasia and deterioration may be present (Table ) [Dordoni et al, ]. The fragility of the capillaries and of the perivascular connective tissues can lead to easy bruising with ecchymosis for minimal traumas both in vEDS and JHS/EDS‐HT patients, though these features are more prominent in vEDS [De Paepe and Malfait, 2004].…”

Section: Differential Diagnosis With Other Eds Types Included In the mentioning

confidence: 99%

“…Concerning cutaneous signs, in vEDS skin is not hyperextensible but rather thin, transparent/translucent, sometimes showing a visible venous pattern over the chest, abdomen and extremities, and fragile with mild atrophic scarring. Acrogeria can be observed in patients harboring specific mutations in COL3A1 [Drera et al, ]. JHM in vEDS generally involves small joints, but can be generalized in some patients.…”

Section: Differential Diagnosis With Other Eds Types Included In the mentioning

confidence: 99%

Differential diagnosis and diagnostic flow chart of joint hypermobility syndrome/ehlers‐danlos syndrome hypermobility type compared to other heritable connective tissue disorders

Colombi¹,

Dordoni²,

Chiarelli³

et al. 2015

American J of Med Genetics Pt C

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Joint hypermobility syndrome/Ehlers-Danlos syndrome hypermobility type (JHS/EDS-HT) is an evolving and protean disorder mostly recognized by generalized joint hypermobility and without a defined molecular basis. JHS/EDS-HT also presents with other connective tissue features affecting a variety of structures and organs, such as skin, eye, bone, and internal organs. However, most of these signs are present in variable combinations and severity in many other heritable connective tissue disorders. Accordingly, JHS/EDS-HT is an "exclusion" diagnosis which needs the absence of any consistent feature indicative of other partially overlapping connective tissue disorders. While both Villefranche and Brighton criteria include such an exclusion as a mandatory item, a systematic approach for reaching a stringent clinical diagnosis of JHS/EDS-HT is still lacking. The absence of a consensus on the diagnostic approach to JHS/EDS-HT concerning its clinical boundaries with similar conditions contribute to limit our actual understanding of the pathologic and molecular bases of this disorder. In this review, we revise the differential diagnosis of JHS/EDS-HT with those heritable connective tissue disorders which show a significant overlap with the former and mostly include EDS classic, vascular and kyphoscoliotic types, osteogenesis imperfecta, Marfan syndrome, Loeys-Dietz syndrome, arterial tortuosity syndrome, and lateral meningocele syndrome. A diagnostic flow chart is also offered with the attempt to support the less experienced clinician in stringently recognizing JHS/EDS-HT and stimulate the debate in the scientific community for both management and research purposes.

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“…All of the three protein prediction software packages considered this variant to be damaging and it was located in a conserved region in COL3A1. This mutation also led to the replacement of one glycine in the (Gly-Xaa-Yaa) n repeat of the collagen triple helix, which was considered pathogenic in various previous studies (3,(14)(15)(16)(17)(18)(19)(20)(21). Thus, G984R in COL3A1 was identified as a pathogenic mutation in the current study.…”

Section: Molecular Genetic Analysismentioning

confidence: 96%

Ehlers-Danlos syndrome type IV is associated with a novel G984R COL3A1 mutation

Deng

Wei

et al. 2012

Molecular Medicine Reports

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Diagnosis of vascular Ehlers-Danlos syndrome in Italy: Clinical findings and novel COL3A1 mutations

Cited by 14 publications

References 9 publications

Transcriptome analysis of skin fibroblasts with dominant negative COL3A1 mutations provides molecular insights into the etiopathology of vascular Ehlers-Danlos syndrome

Transcriptome analysis of skin fibroblasts with dominant negative COL3A1 mutations provides molecular insights into the etiopathology of vascular Ehlers-Danlos syndrome

Differential diagnosis and diagnostic flow chart of joint hypermobility syndrome/ehlers‐danlos syndrome hypermobility type compared to other heritable connective tissue disorders

Ehlers-Danlos syndrome type IV is associated with a novel G984R COL3A1 mutation

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