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COL3A1 haploinsufficiency results in a variety of Ehlers-Danlos syndrome type IV with delayed onset of complications and longer life expectancy.

Published on Aug 1, 2011in Genetics in Medicine8.683
· DOI :10.1097/GIM.0b013e3182180c89
Dru F. Leistritz10
Estimated H-index: 10
(UW: University of Washington),
Melanie G. Pepin23
Estimated H-index: 23
(UW: University of Washington)
+ 1 AuthorsPeter H. Byers70
Estimated H-index: 70
(UW: University of Washington)
Sources
Abstract
Purpose: To characterize the clinical outcome of heterozygosity for COL3A1 null mutations in Ehlers-Danlos syndrome type IV, the vascular type. Methods: We identified mutations that produced premature termination codons and resulted in nonsense-mediated messenger RNA decay in 19 families. We reviewed the clinical and family histories and medical complications in 54 individuals from these families with COL3A1 null mutations. Results: Compared with individuals with missense or exon-skipping mutations, we found that life span was extended, the age of first complication was delayed by almost 15 years, and major complications were limited to vascular events. The families were ascertained after a complication in a single individual, but only 28% of relatives, some of whom had reached their seventies or eighties without incidents, had a complication and only 30% had minor clinical features of Ehlers-Danlos syndrome type IV Conclusion: Null mutations have reduced penetrance compared with missense and splicing mutations, and the phenotype seems to be limited almost entirely to vascular events.
  • References (10)
  • Citations (60)
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References10
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#1Timothy K. Cooper (PSU: Pennsylvania State University)H-Index: 16
#2Q. Zhong (PSU: Pennsylvania State University)H-Index: 1
Last. Wilfried Briest (Leipzig University)H-Index: 5
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Vascular Ehlers-Danlos syndrome is a rare genetic disorder resulting from mutations in the a-1 chain of type III collagen (COL3A1) and manifesting as tissue fragility with spontaneous rupture of the bowel, gravid uterus, or large or medium arteries. The heterozygous Col3a1 knockout mouse was investigated as a model for this disease. The collagen content in the abdominal aorta of heterozygotes was reduced, and functional testing revealed diminishing wall strength of the aorta in these mice. Colon...
25 CitationsSource
#1Z. Khalique (Guy's and St Thomas' NHS Foundation Trust)H-Index: 1
#2Oliver Lyons (Guy's and St Thomas' NHS Foundation Trust)H-Index: 12
Last. Peter R. Taylor (Guy's and St Thomas' NHS Foundation Trust)H-Index: 36
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Abstract A 61-year-old man presented with an acute type B aortic dissection for which a stent-graft was introduced. He remains complication-free 4 years onwards and has since been diagnosed with Ehlers–Danlos syndrome type IV (EDS IV). His particular mutation is predicted to result in lesser levels of normal collagen and may explain his favourable outcome from endovascular intervention. Understanding the genotype–phenotype correlation may influence the choice of therapy offered to patients with ...
19 CitationsSource
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...
33 CitationsSource
#1Ulrike Schwarze (UW: University of Washington)H-Index: 30
#2Wouter I. Schievink (UCI: University of California, Irvine)H-Index: 5
Last. Peter H. Byers (UW: University of Washington)H-Index: 70
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Mutations in the COL3A1 gene that encodes the chains of type III procollagen result in the vascular form of Ehlers-Danlos syndrome (EDS), EDS type IV, if they alter the sequence in the triple-helical domain. Although other fibrillar collagen–gene mutations that lead to allele instability or failure to incorporate proα-chains into trimers—and that thus reduce the amount of mature molecules produced—result in clinically apparent phenotypes, no such mutations have been identified in COL3A1. Further...
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#2Ulrike Schwarze (UW: University of Washington)H-Index: 30
Last. Peter H. Byers (UW: University of Washington)H-Index: 70
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Summary Most splice-site mutations lead to a limited array of products, including exon skipping, use of cryptic splice-acceptor or -donor sites, and intron inclusion. At the intron 8 splice-donor site of the COL1A1 gene, we identified a G+1→A transition that resulted in the production of several splice products from the mutant allele. These included one in which the upstream exon 7 was extended by 96 nt, others in which either intron 8 or introns 7 and 8 were retained, one in which exon 8 was sk...
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Summary Ehlers-Danlos syndrome (EDS) type IV results from mutations in the COL3A1 gene, which encodes the constituent chains of type III procollagen. We have identified, in 33 unrelated individuals or families with EDS type IV, mutations that affect splicing, of which 30 are point mutations at splice junctions and 3 are small deletions that remove splice-junction sequences and partial exon sequences. Except for one point mutation at a donor site, which leads to partial intron inclusion, and a si...
53 CitationsSource
Type III collagen is a fibrillar forming collagen comprising three α1(III) chains and is expressed in early embryos and throughout embryogenesis. In the adult, type III collagen is a major component of the extracellular matrix in a variety of internal organs and skin. Mutations in the COL3A1 gene have been implicated as a cause of type IV Ehlers–Danlos syndrome, a disease leading to aortic rupture in early adult life. To directly study the role of Col3a1 in development and disease, we have inact...
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#1Raymond Dalgleish (University of Leicester)H-Index: 24
Type I collagen is the most abundant and ubiquitously distributed of the collagen family of proteins. It is a heterotrimer comprising two alpha1(I) chains and one alpha2(I) chain which are encoded by the unlinked loci COL1A1 and COL1A2 respectively. Mutations at these loci result primarily in the connective tissue disorders osteogenesis imperfecta and Ehlers-Danlos syndrome types VIIA and VIIB. Two instances of osteoporosis and a single instance of Marfan syndrome are also the result of mutation...
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Thoracic aortic aneurysm and dissection (TAAD) affects many patients globally and has high mortality rates if undetected. Once thought to be solely a degenerative disease that afflicted the aorta due to high pressure and biomechanical stress, extensive investigation of the heritability and natural history of TAAD has shown a clear genetic basis for the disease. Here, we review both the cellular mechanisms and clinical manifestations of syndromic and non-syndromic TAAD. We particularly focus on g...
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Abstract Objective Vascular Ehlers-Danlos syndrome (vEDS) is a rare disorder and 1 of 13 types of EDS. The syndrome results in aortic and arterial aneurysms and dissections at a young age. Diagnosis is confirmed with molecular testing via skin biopsy or genetic testing for COL3A1 pathogenic variants. We describe a multi-institutional experience in the diagnosis of vEDS from 2000 to 2015. Methods This is a multi-institutional cross-sectional retrospective study of individuals with vEDS. The insti...
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Abstract Collagens and elastin are ‘building blocks’ of tissues and extracellular matrix. Mutations in these proteins cause severe congenital syndromes. Adverse genetic variations may accelerate the aging process in adults contributing to premature morbidity, disability and/or mortality. Favorable variants may contribute to longevity and/or healthy aging, but this is much less studied. We reviewed the association between variation in the genes of collagens and elastin and premature aging, accele...
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#1Sherene Shalhub (UW: University of Washington)H-Index: 13
#2Liz Sage (UW: University of Washington)H-Index: 1
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Abstract Objective Patient centered research requires active engagement of patients. The Vascular Ehlers-Danlos Syndrome (vEDS) research collaborative was established to ascertain patient-centered vEDS research priorities and to engage affected individuals as research partners. Evaluation of access to information and interest in research among individuals with vEDS was the first step undertaken as part of this work. Methods A 28 question survey was created to evaluate four domains of interest: D...
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#1Caitlin J. Bowen (HHMI: Howard Hughes Medical Institute)
#1Caitlin J. Bowen (HHMI: Howard Hughes Medical Institute)
Last. Harry C. DietzH-Index: 90
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Vascular Ehlers-Danlos syndrome (vEDS) is an autosomal-dominant connective tissue disorder caused by heterozygous mutations in the COL3A1 gene, which encodes the pro-alpha 1 chain of collagen III. Loss of structural integrity of the extracellular matrix is believed to drive the signs and symptoms of this condition, including spontaneous arterial dissection and/or rupture, the major cause of mortality. We created 2 mouse models of vEDS that carry heterozygous mutations in Col3a1 that encode glyci...
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#1Matthew R. Lavoie (Madigan Army Medical Center)
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We report a case of a 35-year-old woman found to have vascular Ehlers-Danlos syndrome (vEDS) after family history of sudden death due to aortic dissection in her otherwise healthy brother prompted further imaging workup and consideration of an underlying heritable genetic condition. CT angiogram of the aorta with intravenous contrast revealed an abdominal aortic artery dissection below the level of the renal arteries extending from the bifurcation into the left common iliac artery with an additi...
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#2Peter H. Byers (UW: University of Washington)H-Index: 70
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Ehlers-Danlos syndromes (EDSs) are a group of heritable connective tissue disorders with distinct genetic etiologies. Of the 13 currently recognized types of EDS, the vascular type EDS (vEDS) is generally considered the most severe and is associated with a decreased life expectancy due to spontaneous arterial, intestinal, and or uterine rupture. Diagnosis of vEDS is supported by genetic testing confirming the presence of pathogenic variations in COL3A1, a type III procollagen gene. Management of...
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