Multiple Defects in Type III Collagen Synthesis Are Associated with the Pathogenesis of Abdominal Aortic Aneurysmsa

Abstract

Confluent skin fibroblast cultures were prepared from 40 patients diagnosed with and surgically treated for an abdominal aortic aneurysm. An analysis of secreted type I and type III collagen in the media of these fibroblast preparations revealed reduced secretion of type III collagen from six patients. DNA sequence analysis of the entire coding domain of the pro alpha 1 (III) collagen mRNA in skin fibroblast RNA from these six patients revealed a C to T substitution at nucleotide 607 in one of the probands that would result in the replacement of a leucine residue with phenylalanine in the second position of the first tripeptide repeat in the triple-helical domain of type III collagen. Allele-specific hybridization analysis of genomic DNA from this proband and family members indicated that this non-glycine substitution probably contributed to the aneurysmal phenotype in this patient. No coding sequence mutations were found in the other five patients. It is clear from this study, therefore, that aberrant synthesis of type III collagen, as a consequence of both a coding sequence mutation and other factors contributing to reduced secretion of type III procollagen, will result in the development of an aortic aneurysm in a significant percentage of patients with this disease.

Genes and Abdominal Aortic Aneurysm

“…Two mutations were detected (G136R and T501P), but they were present in only 2% of AAA patients 16. Another study examined the COL3A1 sequences in 40 AAA patients with 22.5% having positive family history and 29 patients with aortic occlusive disease 13. Only one patient among the 40 AAA patients was found with a mutation (607C>T, which replaces a leucine with phenylalanine) in the coding region of COL3A1 13.…”

“…Another study examined the COL3A1 sequences in 40 AAA patients with 22.5% having positive family history and 29 patients with aortic occlusive disease 13. Only one patient among the 40 AAA patients was found with a mutation (607C>T, which replaces a leucine with phenylalanine) in the coding region of COL3A1 13. In conclusion, mutations in the COL3A1 can be found in only a small fraction of AAA patients, most likely in patients who have an undiagnosed Ehlers-Danlos syndrome type IV.…”

“…Subsequent candidate gene studies in single AAA families with several affected individuals identified mutations in connective tissue genes 13–16. These mutations, however, were not seen in sporadic AAA patients.…”

Abdominal Aortic Aneurysm Is a Specific Antigen‐Driven T Cell Disease

“…21 However, many questions remain to be answered to determine whether AAA is an autoimmune disease. It is not known whether the inflammatory response is antigen-driven, although a number of putative self-and nonself antigens have been suggested including elastin and elastin fragments, [24][25][26][27] oxidized low-density lipoprotein (LDL), 28,29 aortic aneurysm antigenic protein-40 (AAA-P), also known as human microbial-associated glycoprotein-36 (MAGP-36), [11][12][13] collagen types 1 and 3, [30][31][32][33] Chlamydia pneumoniae, [34][35][36][37] cytomegalovirus, 38 and Treponema palladium. 39 Molecular mimicry (Oleszak et al 40 ) may be responsible for the induction of T cell inflammatory responses in AAA lesions.…”

Human autoimmune diseases are specific antigen-driven T-cell diseases: identification of the antigens

“…elastin and elastin fragments [75][76][77], collagen types I and III [78], oxidized low density lipoprotein (LDL) [79], aortic aneurism antigenic protein-40 (AAA-P) [70,71], chlamydia [80][81][82], Treponema palladium [83] and cytomegalovirus [84].…”