A novel genetic locus modulates infarct volume independently of the extent of collateral circulation.

Abstract:

:In the mouse model of permanent, middle cerebral artery occlusion, infarct volume varies widely across inbred strains but generally is inversely correlated with collateral vessel number. However, we also observed certain mouse strains that share similar collateral vessel anatomy but exhibit significantly different infarct volume. To identify genetic factors determining infarct volume in a collateral vessel-independent manner, we performed quantitative trait locus analysis on a F2 cross between C57BL/6J and C3H/HeJ strains. We mapped four novel loci (Civq4 through Civq7) that modulate infarct volume. Civq4, on chromosome 8, is the strongest locus (logarithm of the odds 9.8) that contributes 21% of the phenotypic variance of infarct volume in the cross. The Civq4 and Civq6 loci represent transgressive B6 alleles that render animals susceptible to larger infarcts. Based on genomic sequence and microarray analyses, we propose candidate genes for the Civq4 locus. By selecting inbred strains with similar collateral vessel anatomy but that vary significantly in infarct volume, we have mapped four loci determining infarct volume in a mouse model of ischemic stroke. Two of the loci appear to modulate infarct volume through a collateral vessel-independent mechanism. Based on strain-specific sequence variants and differences in transcript levels, Msr1 and Mtmr7 appear to be strong candidate genes for Civq4. Identifying the underlying genetic factors of these loci will elucidate the genetic architecture response to cerebral ischemia, shed new light on disease mechanisms of ischemic stroke, and identify potential therapeutic targets for clinical applications.

journal_name

Physiol Genomics

journal_title

Physiological genomics

authors

Chu PL,Keum S,Marchuk DA

doi

10.1152/physiolgenomics.00063.2013

subject

Has Abstract

pub_date

2013-09-03 00:00:00

pages

751-63

issue

17

eissn

1094-8341

issn

1531-2267

pii

physiolgenomics.00063.2013

journal_volume

45

pub_type

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