Abstract
ABSTRACTCollagen 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.
Highlights
Collagens comprise a large family of extracellular matrix proteins, which play a key role in the tissue integrity of all organs
We have demonstrated a functional role for Col22a1 in maintaining vascular stability in the zebrafish model system
Further genetic analysis using larger patient samples is needed to confirm the association of mutations in COL22A1 with intracranial aneurysms
Summary
Collagens comprise a large family of extracellular matrix proteins, which play a key role in the tissue integrity of all organs. The blood vessel wall contains subendothelial basement membrane, intima, media, adventitia and interstitial matrix layers Each of these layers contains multiple types of collagens, which are crucial for vascular stability and structural integrity. Collagen IV is a major component of the basement membrane, and mutations in human COL4A1 have been associated with a variety of syndromes, including intracranial aneurysms and cerebral hemorrhages (Volonghi et al, 2010). Collagen COL22A1 maintains vascular stability and mutations in COL22A1 are potentially associated with intracranial aneurysms genetic and environmental factors have been implicated in susceptibility to stroke. We reanalyzed the original data from the WES study of familial IAs (Farlow et al, 2015) and identified the rs142175725 SNP present in all affected individuals in one of the families, which is predicted to result in a E736D substitution within the COL22A1 protein sequence. Our results identify a novel role for Col22a1 in maintaining vascular stability and suggest that mutations in COL22A1 could be one of the causes of intracranial aneurysms
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