COL3A1 mutations cause variable clinical phenotypes including acrogeria and vascular rupture

Pope, F M; Narcisi, P; Nicholls, A C; Germaine, D; Pals, Gerard; Richards, Allan J.

doi:10.1111/j.1365-2133.1996.tb01143.x

Cited by 105 publications

(44 citation statements)

References 28 publications

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“…Genotype–phenotype correlation in patients with vascular EDS is not always clear cut, with intra‐ and inter‐family variability widely recognized. Glycine substitutions which disrupt collagen helix formation are commonly associated with significant vascular risk and an easily recognizable clinical phenotype [Pope et al, ]. Recent reports have correlated the degree of collagen (III) deficiency with age of onset of vascular complications [Shalhub et al, ].…”

Section: Discussionmentioning

confidence: 99%

Clinical, structural, biochemical and X‐ray crystallographic correlates of pathogenicity for variants in the C‐propeptide region of the COL3A1 gene

Stembridge

Vandersteen

Ghali

et al. 2015

American J of Med Genetics Pt A

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Vascular Ehlers-Danlos syndrome (vEDS) is a heritable disorder of connective tissue caused by pathological variants in the COL3A1 gene, which encodes the α1 chain of type III collagen. Type III collagen is a major component of skin, arterial walls, and the gastrointestinal tract. Collagen III protein deficiency manifests as an increased risk of rupture, perforation, and dissection of these structures. The most disruptive gene variants affect the collagen helix via glycine substitutions or splice donor site mutations. The C-propeptide region of COL3A1 includes exons 49-52 and has a crucial role in initiating the C-terminal assembly of procollagen monomers in the early stages of collagen biosynthesis. Nineteen COL3A1 variants have previously been reported in these exons, of which four were associated with a severe vEDS phenotype. We identified two novel C-propeptide missense variants; p.Pro1440Leu, p.Arg1432Leu, and a non-stop mutation, c.4400A > T, p. (*1467Leuext*45). These variants produce variable phenotypes ranging from obvious acrogeria to classical or hypermobile EDS. A previously reported variant p.Lys1313Arg is of unknown clinical significance but likely benign, based on this study. Assigning disease pathogenicity remains complex, clinical phenotyping and crystal structure evidence being crucial. We briefly compare reported phenotypes for patients with missense variants in the C-propeptide domain for other human collagen disorders including COL1A1 and COL1A2 (osteogenesis imperfecta).

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Section: Discussionmentioning

confidence: 99%

Clinical, structural, biochemical and X‐ray crystallographic correlates of pathogenicity for variants in the C‐propeptide region of the COL3A1 gene

Stembridge

Vandersteen

Ghali

et al. 2015

American J of Med Genetics Pt A

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“…One candidate gene to be considered is the collagen III gene, as Pope et al [29]found 23 mutations of the collagen III gene (COL3A1) in acrogeria with pronounced vascular rupture. Premature arterial fragility and skin thinning also occur in vascular variants of Ehlers-Danlos syndrome caused by mutations in the COL3A1 gene [29].…”

Section: Discussionmentioning

confidence: 99%

“…Premature arterial fragility and skin thinning also occur in vascular variants of Ehlers-Danlos syndrome caused by mutations in the COL3A1 gene [29]. Especially 3′ mutations of the triple-helical coding region of the COL3A1 gene lead to an acrogeric phenotype with thinning of the skin and capillary telangiectasia, while 5′ or middle helical exon skips are phenotypically discrete [30].…”

Section: Discussionmentioning

confidence: 99%

Predominant Telangiectatic Erythema in Linear Atrophoderma of Moulin: Novel Variant or Separate Entity?

Utikal

Keil²,

Klemke³

et al. 2003

Dermatology

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Linear atrophoderma of Moulin is a distinctive disease originally described in 1992 and characterized by acquired, mildly atrophic, non-sclerotic, slightly hyperpigmented lesions following the lines of Blaschko. Here, we describe a 15-year-old girl with a 13-year history and a 29-year-old male with a 6-year history of prominent linear telangiectatic erythema and mild atrophoderma following the lines of Blaschko that involved the right leg and hip, and both legs, the trunk and both arms, respectively. As pronounced telangiectatic erythema within lesions of atrophoderma of Moulin has not hitherto been described, we propose that the disease in our patients represents a novel variant of linear atrophoderma of Moulin. Due to considerable overlap, we do not favour the notion that our cases constitute an entity entirely separate from linear atrophoderma of Moulin.

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“…Accordingly, the unique mutation found in the present patient should be considered to be pathogenic. Recent reports indicated that the mutant region of the type III collagen might reflect clinical severity of the phenotype in terms of prognosis [10–13]. There are many reports that the position of the mutation in COL3A1 may play a role in a common natal complication for each family, such as subarachnoid haemorrhage [14], intraperitoneal bleeding [15] or spontaneous perforation of the iliac artery [8].…”

Section: Discussionmentioning

confidence: 99%

Ehlers–Danlos syndrome type IV with a unique point mutation in COL3A1 and familial phenotype of myocardial infarction without organic coronary stenosis

Nishiyama

Nejima

Watanabe

et al. 2001

Journal of Internal Medicine

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Abstract. Nishiyama Y, Nejima J, Watanabe A, Kotani E, Sakai N, Hatamochi A, Shinkai H, Kiuchi K, Tamura K, Shimada T, Takano T, Katayama Y (Nippon Medical School, Tokyo, and Chiba University School of Medicine, Chiba, Japan). Ehlers±Danlos syndrome type IV with a unique point mutation in COL3 A1 and familial phenotype of myocardial infarction without organic coronary stenosis (Case Report). J Intern Med 2001; 249: 103±108.We report on a 43-year-old male patient with Ehlers± Danlos syndrome (EDS) type IV with acute myocardial infarction (MI) without organic coronary stenosis. The disease was complicated with pneumothorax, subcutaneous and mediastinal emphysema, and splenic artery rupture. Three of the patient's family members suffered sudden cardiac death or MI. A diagnosis of EDS type IV was confirmed by decreased production of type III collagen by 86%. Mutation analysis revealed a point mutation in the COL3A1 gene that substituted glycine for aspartate at amino acid position 877. This mutation had not been reported as pathogenic for EDS type IV. These findings suggest close linkage between the mutation and the phenotype with familial MI.

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COL3A1 mutations cause variable clinical phenotypes including acrogeria and vascular rupture

Cited by 105 publications

References 28 publications

Clinical, structural, biochemical and X‐ray crystallographic correlates of pathogenicity for variants in the C‐propeptide region of the COL3A1 gene

Clinical, structural, biochemical and X‐ray crystallographic correlates of pathogenicity for variants in the C‐propeptide region of the COL3A1 gene

Predominant Telangiectatic Erythema in Linear Atrophoderma of Moulin: Novel Variant or Separate Entity?

Ehlers–Danlos syndrome type IV with a unique point mutation in COL3A1 and familial phenotype of myocardial infarction without organic coronary stenosis

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