Collagen COL22A1 maintains vascular stability and mutations in COL22A1 are potentially associated with intracranial aneurysms

Quynh V. Ton, Daniel Leino, Sarah A. Mowery, Nina O. Bredemeier, Pascal J. Lafontant, Allison Lubert, Suman Gurung, Janice L. Farlow, Tatiana Foroud, Joseph Broderick, Saulius Sumanas

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Collagen XXII (COL22A1) is a quantitatively minor collagen, which belongs to the family of fibril-associated collagens with interrupted triple helices. Its biological function has been poorly understood. Here, we used a genome-editing approach to generate a loss-of-function mutant in zebrafish col22a1 Homozygous mutant adults exhibit increased incidence of intracranial hemorrhages, which become more prominent with age and after cardiovascular stress. Homozygous col22a1 mutant embryos show higher sensitivity to cardiovascular stress and increased vascular permeability, resulting in a greater percentage of embryos with intracranial hemorrhages. Mutant embryos also exhibit dilations and irregular structure of cranial vessels. To test whether COL22A1 is associated with vascular disease in humans, we analyzed data from a previous study that performed whole-exome sequencing of 45 individuals from seven families with intracranial aneurysms. The rs142175725 single-nucleotide polymorphism was identified, which segregated with the phenotype in all four affected individuals in one of the families, and affects a highly conserved E736 residue in COL22A1 protein, resulting in E736D substitution. Overexpression of human wild-type COL22A1, but not the E736D variant, partially rescued the col22a1 loss-of-function mutant phenotype in zebrafish embryos. Our data further suggest that the E736D mutation interferes with COL22A1 protein secretion, potentially leading to endoplasmic reticulum stress. Altogether, these results argue that COL22A1 is required to maintain vascular integrity. These data further suggest that mutations in COL22A1 could be one of the risk factors for intracranial aneurysms in humans.

Original languageEnglish (US)
JournalDisease models & mechanisms
Volume11
Issue number12
DOIs
StatePublished - Dec 12 2018

Fingerprint

Intracranial Aneurysm
Blood Vessels
Collagen
Embryonic Structures
Mutation
Intracranial Hemorrhages
Fibril-Associated Collagens
Zebrafish
Exome
Polymorphism
Phenotype
Endoplasmic Reticulum Stress
Capillary Permeability
Proteins
Substitution reactions
Nucleotides
Genes
Vascular Diseases
Single Nucleotide Polymorphism
Dilatation

Keywords

  • Collagen
  • Intracranial aneurysms
  • Vascular integrity
  • Zebrafish

ASJC Scopus subject areas

  • Neuroscience (miscellaneous)
  • Medicine (miscellaneous)
  • Immunology and Microbiology (miscellaneous)
  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Collagen COL22A1 maintains vascular stability and mutations in COL22A1 are potentially associated with intracranial aneurysms. / Ton, Quynh V.; Leino, Daniel; Mowery, Sarah A.; Bredemeier, Nina O.; Lafontant, Pascal J.; Lubert, Allison; Gurung, Suman; Farlow, Janice L.; Foroud, Tatiana; Broderick, Joseph; Sumanas, Saulius.

In: Disease models & mechanisms, Vol. 11, No. 12, 12.12.2018.

Research output: Contribution to journalArticle

Ton, QV, Leino, D, Mowery, SA, Bredemeier, NO, Lafontant, PJ, Lubert, A, Gurung, S, Farlow, JL, Foroud, T, Broderick, J & Sumanas, S 2018, 'Collagen COL22A1 maintains vascular stability and mutations in COL22A1 are potentially associated with intracranial aneurysms', Disease models & mechanisms, vol. 11, no. 12. https://doi.org/10.1242/dmm.033654
Ton, Quynh V. ; Leino, Daniel ; Mowery, Sarah A. ; Bredemeier, Nina O. ; Lafontant, Pascal J. ; Lubert, Allison ; Gurung, Suman ; Farlow, Janice L. ; Foroud, Tatiana ; Broderick, Joseph ; Sumanas, Saulius. / Collagen COL22A1 maintains vascular stability and mutations in COL22A1 are potentially associated with intracranial aneurysms. In: Disease models & mechanisms. 2018 ; Vol. 11, No. 12.
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AU - Bredemeier, Nina O.

AU - Lafontant, Pascal J.

AU - Lubert, Allison

AU - Gurung, Suman

AU - Farlow, Janice L.

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AU - Broderick, Joseph

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