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Natural genetic variation of integrin alpha L (Itgal) modulates ischemic brain injury in stroke.

Publication ,  Journal Article
Keum, S; Lee, HK; Chu, P-L; Kan, MJ; Huang, M-N; Gallione, CJ; Gunn, MD; Lo, DC; Marchuk, DA
Published in: PLoS Genet
2013

During ischemic stroke, occlusion of the cerebrovasculature causes neuronal cell death (infarction), but naturally occurring genetic factors modulating infarction have been difficult to identify in human populations. In a surgically induced mouse model of ischemic stroke, we have previously mapped Civq1 to distal chromosome 7 as a quantitative trait locus determining infarct volume. In this study, genome-wide association mapping using 32 inbred mouse strains and an additional linkage scan for infarct volume confirmed that the size of the infarct is determined by ancestral alleles of the causative gene(s). The genetically isolated Civq1 locus in reciprocal recombinant congenic mice refined the critical interval and demonstrated that infarct size is determined by both vascular (collateral vessel anatomy) and non-vascular (neuroprotection) effects. Through the use of interval-specific SNP haplotype analysis, we further refined the Civq1 locus and identified integrin alpha L (Itgal) as one of the causative genes for Civq1. Itgal is the only gene that exhibits both strain-specific amino acid substitutions and expression differences. Coding SNPs, a 5-bp insertion in exon 30b, and increased mRNA and protein expression of a splice variant of the gene (Itgal-003, ENSMUST00000120857), all segregate with infarct volume. Mice lacking Itgal show increased neuronal cell death in both ex vivo brain slice and in vivo focal cerebral ischemia. Our data demonstrate that sequence variation in Itgal modulates ischemic brain injury, and that infarct volume is determined by both vascular and non-vascular mechanisms.

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Published In

PLoS Genet

DOI

EISSN

1553-7404

Publication Date

2013

Volume

9

Issue

10

Start / End Page

e1003807

Location

United States

Related Subject Headings

  • Stroke
  • Quantitative Trait Loci
  • Polymorphism, Single Nucleotide
  • Mice
  • Integrin alpha Chains
  • Humans
  • Haplotypes
  • Genome-Wide Association Study
  • Genetic Linkage
  • Disease Models, Animal
 

Citation

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Keum, S., Lee, H. K., Chu, P.-L., Kan, M. J., Huang, M.-N., Gallione, C. J., … Marchuk, D. A. (2013). Natural genetic variation of integrin alpha L (Itgal) modulates ischemic brain injury in stroke. PLoS Genet, 9(10), e1003807. https://doi.org/10.1371/journal.pgen.1003807
Keum, Sehoon, Han Kyu Lee, Pei-Lun Chu, Matthew J. Kan, Min-Nung Huang, Carol J. Gallione, Michael D. Gunn, Donald C. Lo, and Douglas A. Marchuk. “Natural genetic variation of integrin alpha L (Itgal) modulates ischemic brain injury in stroke.PLoS Genet 9, no. 10 (2013): e1003807. https://doi.org/10.1371/journal.pgen.1003807.
Keum S, Lee HK, Chu P-L, Kan MJ, Huang M-N, Gallione CJ, et al. Natural genetic variation of integrin alpha L (Itgal) modulates ischemic brain injury in stroke. PLoS Genet. 2013;9(10):e1003807.
Keum, Sehoon, et al. “Natural genetic variation of integrin alpha L (Itgal) modulates ischemic brain injury in stroke.PLoS Genet, vol. 9, no. 10, 2013, p. e1003807. Pubmed, doi:10.1371/journal.pgen.1003807.
Keum S, Lee HK, Chu P-L, Kan MJ, Huang M-N, Gallione CJ, Gunn MD, Lo DC, Marchuk DA. Natural genetic variation of integrin alpha L (Itgal) modulates ischemic brain injury in stroke. PLoS Genet. 2013;9(10):e1003807.

Published In

PLoS Genet

DOI

EISSN

1553-7404

Publication Date

2013

Volume

9

Issue

10

Start / End Page

e1003807

Location

United States

Related Subject Headings

  • Stroke
  • Quantitative Trait Loci
  • Polymorphism, Single Nucleotide
  • Mice
  • Integrin alpha Chains
  • Humans
  • Haplotypes
  • Genome-Wide Association Study
  • Genetic Linkage
  • Disease Models, Animal