Spontaneous multivessel cervical artery dissection in a patient with a substitution of alanine for glycine (G13A) in the alpha 1(I) chain of type I collagen

Mayer, Stephan A.; Rubin, Bruce; Starman, Barbra J.; Byers, Peter H.

doi:10.1212/wnl.47.2.552

Cited by 84 publications

(49 citation statements)

References 14 publications

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“…We furthermore analyzed the sequences of exons 4 to 10 of COL1A1, because in a singular CAD patient with minor signs of OI, a mutation had been found in exon 6. 29 A COL3A1 missense mutation was detected in both affected patients from family 1, as well as in the 2 patients' mothers (who are sisters). Clinical signs of connective tissue weakness were absent and skin biopsy findings were normal.…”

Section: Martin Et Al Familial Cervical Artery Dissections 2927mentioning

confidence: 96%

Familial Cervical Artery Dissections

Martin

Haußer

Lyrer

et al. 2006

Stroke

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Background and Purpose-Genetic risk factors are thought to play a role in the etiology of spontaneous cervical artery dissections (CAD). However, familial CAD is extremely rare. In this study we analyzed patients with familial CAD and asked the question whether familial CAD has particular features. Methods-Seven families with 15 CAD patients were recruited. All patients were carefully investigated by a neurologist, a neuroradiologist, and a dermatologist for clinical characteristics. From 11 patients a skin biopsy was performed to study the morphology of the connective tissue and to analyze the coding sequences of COL3A1, COL5A1, COL5A2, and part of COL1A1. Results-The mean age of the patients (nϭ15, 9 women) at their first dissection was 36.2 years (median age 32 years, range 18 to 59). Two patients had bilateral CAD. One patient had a right and a left internal carotid artery dissection in successive weeks, another patient had 5 dissections over a period of 8 years. A high intrafamilial correlation was found between the affected vessels (ie, the carotid and the vertebral arteries) and between ages at the first dissection. In 1 patient we found clear and reproducible ultrastructural abnormalities in the skin biopsy, but the second patient from the family was not studied, because he died as a result of CAD before this study. The dermal connective tissue aberrations in the examined patient were similar to mild findings in patients with vascular Ehlers-Danlos syndrome (EDS type IV), but might be iatrogenic and related to long-term corticosteroid inhalation therapy. All other analyzed patients showed normal connective tissue morphology. In patients from 6 families we analyzed the whole coding sequence of COL3A1, COL5A1, and COL5A2, and from part of COL1A1. A missense mutation in the COL3A1 gene (leading to a G157S substitution in type III procollagen) was detected in both patients from 1e family. Two patients from another family carried a rare nonsynonymous coding polymorphism in COL5A1 (D192N); 1 of them carried also a rare variant in COL5A2 (T12337). Conclusions-Familial CAD patients are young and probably are at high risk for recurrent or multiple CAD.Ultrastructural alterations of the dermal connective tissue might not be an important risk factor for familial CAD. However, the finding of a COL3A1 mutation revealed the presence of an inherited connective tissue disorder in 1 family.

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Section: Martin Et Al Familial Cervical Artery Dissections 2927mentioning

confidence: 96%

Familial Cervical Artery Dissections

Martin

Haußer

Lyrer

et al. 2006

Stroke

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“…However, patients occasionally develop dissection of the aorta 16 and other large vessels. 17 Although a targeted disruption of the Col1a1 gene has not been performed, the random insertion of the Molony murine leukemia virus into the first intron of Col1a1 inactivated the gene in most tissues, including blood vessels. 18,19 These mice die at day 11 to 14 of embryonic age from rupture of blood vessels.…”

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confidence: 99%

Mice With a Deletion in the First Intron of the Col1a1 Gene Develop Age-Dependent Aortic Dissection and Rupture

Rahkonen

Hakovirta

et al. 2004

Circulation Research

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Abstract-The functional significance of the first intron of the Col1a1 gene in regulation of type I collagen synthesis remains uncertain. A previous study in mice established that a mutated Col1a1 allele that lacked a large fraction of the first intron, but retained the sequences required for normal splicing, was subject to an age-and tissue-dependent decrease in expression. In this study, we report that mice homozygous for this deletion are predisposed to dissection and rupture of the aorta during their adult life. Aortic dissection was not detected in autopsies of heterozygous animals or their littermate controls. Electron micrographs revealed fewer collagen fibrils and less compacted, irregular elastic lamellae in the aortic walls of homozygous mutant animals. Northern analysis of aortic RNA from 2.5-and 12-month-old homozygous mutant mice revealed that Col1a1 mRNA levels were decreased by 29% and 42%, respectively, relative to those of control littermates. In 12-month-old heterozygotes, the decrease was 32%. Allele-specific amplification of heterozygous cDNAs demonstrated that this reduction was limited to transcripts from the mutant allele. The collagen content of the aortas of homozygous mutant mice was also significantly lower in comparison to that of age-matched, control animals. These data establish that the integrity of the aortic wall depends on an adequate content of type I collagen, and that continued synthesis of collagen in the aorta as a function of age is critically dependent on sequences in the first intron of the Col1a1 gene. Key Words: collagen Ⅲ gene regulation Ⅲ targeted mutation Ⅲ RT-PCR Ⅲ homologous recombination T ype I collagen is the main component of fibrils that provide tissues with tensile strength. To achieve the highly variable levels of type I collagen in different tissues during development, growth, aging, and tissue repair, the genes encoding the constituent ␣1 and ␣2 chains of type I collagen (Col1a1 and Col1a2) are likely to be under complex transcriptional and posttranscriptional control. Both positively and negatively acting genomic elements that are involved in tissue-specific transcriptional control have indeed been identified in the upstream promoter region of the Col1a1 gene, 1-3 and also exist in the first intron. 4,5 These elements mediate the complex effects of cytokines and growth factors. 6 -8 Hormuzdi and coworkers 9 generated a mouse line with a large deletion in the first intron of the Col1a1 gene (herein termed Col-Int⌬ or ⌬/⌬ mice) that did not impair normal splicing of the shortened intron. As a function of age, the expression of the mutated allele was reduced by about 50% from its control level in lung and skeletal muscle. Nevertheless, both in cell culture and in response to bleomycin-induced fibrosis, cells expressing the mutant allele were able to increase collagen gene transcription to levels approaching that of the wild-type allele. 9,10 Thus, the mutant allele in ⌬/⌬ mice can respond to physiological signals, and these signals can override the inhibi...

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“…15 However, all have typical findings of the skin and the body structure and could be ruled out in the present case because of the patient's history and physical examination. Mayer et al reported one case of spontaneous multivessel cervical artery dissection in a patient who had a mutation in the type I collagen gene and no family history of arterial dissection, 16 and that case can be considered as a mild phenotypic variant of osteogenesis imperfecta, which should be also included in the differential diagnosis of the present case. Another possible diagnosis is eosinophilic arteritis, which is also complicated by multiple arterial dissections, 17 but is unlikely in the present case because the signs and symptoms of chronic systemic inflammatory disease were absent before the onset of renal infarction, and because eosinophilia did not occur during the clinical course.…”

Section: Discussionmentioning

confidence: 78%

Spontaneous Multiple Arterial Dissections Presenting With Renal Infarction and Subarachnoid Hemorrhage in a Patient Under Treatment for Infertility

Wakino

Tawarahara

Tsuchiya

et al. 2005

Circ J

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A 36-year-old woman developed multiple spontaneous arterial dissections in both renal arteries, the carotid artery, superior mesenteric artery, and vertebral artery, but not the aorta, and she suffered a renal infarction and subarachnoid hemorrhage within a short period of time. She had been undergoing frequent injections of human chorionic gonadotropin and human menopausal gonadotropin, together with oral estrogen therapy, during a 5-year infertility treatment regimen. As she had no other history of any disorder affecting the arterial walls, this therapy is suspected to have caused the multiple arterial deformities. Although cases of isolated arterial dissection are occasionally reported, it is rare for multiple dissections and serious symptoms to occur simultaneously. (Circ J 2005; 69: 368 -372)

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Spontaneous multivessel cervical artery dissection in a patient with a substitution of alanine for glycine (G13A) in the alpha 1(I) chain of type I collagen

Cited by 84 publications

References 14 publications

Familial Cervical Artery Dissections

Familial Cervical Artery Dissections

Mice With a Deletion in the First Intron of the Col1a1 Gene Develop Age-Dependent Aortic Dissection and Rupture

Spontaneous Multiple Arterial Dissections Presenting With Renal Infarction and Subarachnoid Hemorrhage in a Patient Under Treatment for Infertility

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