Analysis of the COL3A1 gene in patients with spontaneous cervical artery dissections

Abstract

The etiology of spontaneous cervical artery dissection (sCAD) is unknown. An underlying connective tissue disorder has been suggested. As a collagen disease is conceivable several genes encoding fibrillar collagens have been condsidered as candidate genes for sCAD. We analysed the COL3A1 gene in patients with spontaneous cervical artery dissection (sCAD) and in healthy controls, using three different genetic methods. 1) The promoter region, the 5' and 3' untranscribed regions and the N- and C- peptide encoding regions were studied by direct sequencing analysis of DNA from 12 patients. 2) A possible association of sCAD and the COL3A1 gene was tested for with 5 different DNA polymorphisms in 45 patients and 50 healthy control subjects. 3) DNA samples from a father and his two daughters, all suffering from spontaneous dissections of a cervical artery, were analysed with CA-repeat markers that flank the COL3A1 locus. No disease-causing mutations were found in an extended sequence analysis of the COL3A1 gene in patients with sCAD. However, we identified a single nucleotid polymorphism (SNP) in the promotor region in 2 patients and a 2 bp deletion in the 3' UTR in 7 patients. These sequence variants were also found among 50 healthy subjects. An analysis of multiple DNA polymorphisms of the COL3A1 locus in patients and healthy control persons did not indicate a significant association of sCAD with COL3A1. A deletion polymorphism in the 3' UTR was, however, found more often amongst patients with sCAD. The possible linkage of a hypothetical disease mutation with the COL3A1 locus was tested in a small family with three affected patients. As the affected daughters did not inherit the same COL3A1 allele from their affected father (LOD < - 2.3) COL3A1 was excluded as a disease gene in this family. This study confirms and extends earlier work which suggests that COL3A1 mutations are not a major cause for isolated sCAD.

The Genetics of Cervical Artery Dissection

“…Five studies reported associations with 3 different candidate genes: ICAM-1, COL3A1, and MTHFR. 8,9,12,51,66 The associations with the ICAM-1 E469K polymorphism and the COL3A1 3ЈUTR 2-bp deletion, 12,51 observed in 2 relatively small studies, have not been replicated and should therefore be interpreted with caution. The ICAM-1 E469K polymorphism could modify the affinity of ICAM-1 to its ligands, which may lead to increased activation of cytokines and proteases, thus inducing extracellular matrix degradation and weakening of the arterial wall.…”

“…One linkage analysis was performed in a family with 3 members affected by CAD using CA repeat markers that flank the COL3A1 locus yielding negative results. 51 Other linkage studies have been performed in families with only one member affected by CAD but several members presenting dermal connective tissue aberrations (intermediate phenotype)…”

“…12 The COL3A1 3ЈUTR 2-bp deletion may influence COL3A1 expression and thus extracellular matrix homeostasis. 51 Three studies found a positive association between the methylenetetrahydrofolate reductase (MTHFR) 677TT genotype and CAD. 8,9,66 Three other studies did not find any significant association between MTHFR 677TT and CAD.…”

A Systematic Review of the Risk Factors for Cervical Artery Dissection

“…[32][33][34]39,47,48 None of the identified mutations, however, was suggested to play a major role in the cause of CAD.…”

Cervical artery dissection

“…We did not attempt genetic analysis because the results in several studies investigating genes causing CTD were negative in patients with SCAD. 2,9 The data on EDS IV suggest that despite following an autosomal-dominant trait, phenotype and age of presentation can vary considerably. 3 New mutations may occur in up to 50%.…”