Genotypes of Stim1 and the proximal region on chromosome 1 exert opposite effects on stroke susceptibility in stroke-prone spontaneously hypertensive rat

<jats:sec> <jats:title>Background:</jats:title> <jats:p>The stroke-prone spontaneously hypertensive rat (SHRSP) is a genetic model for cerebral stroke. Although a recent study on a congenic SHRSP suggested that a nonsense mutation in stromal interaction molecule 1 (<jats:italic toggle="yes">Stim1</jats:italic>) encoding a major component of store-operated Ca<jats:sup>2+</jats:sup> entry was a causal variant for stroke in SHRSP, this was not conclusive because the congenic region including <jats:italic toggle="yes">Stim1</jats:italic> in that rat was too wide. On the other hand, we demonstrated that the Wistar–Kyoto (WKY)-derived congenic fragment adjacent to <jats:italic toggle="yes">Stim1</jats:italic> exacerbated stroke susceptibility in a congenic SHRSP called SPwch1.71. In the present study, we directly examined the effects of the <jats:italic toggle="yes">Stim1</jats:italic> genotype on stroke susceptibility using SHRSP in which wild-type <jats:italic toggle="yes">Stim1</jats:italic> was knocked in (called <jats:italic toggle="yes">Stim1</jats:italic>-KI SHRSP). The combined effects of <jats:italic toggle="yes">Stim1</jats:italic> and the congenic fragment of SPwch1.71 were also investigated.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods:</jats:title> <jats:p>Stroke susceptibility was assessed by the stroke symptom-free and survival periods based on observations of behavioral symptoms and reductions in body weight.</jats:p> </jats:sec> <jats:sec> <jats:title>Results:</jats:title> <jats:p> <jats:italic toggle="yes">Stim1</jats:italic>-KI SHRSP was more resistant to, while SPwch1.71 was more susceptible to stroke than the original SHRSP. Introgression of the wild-type <jats:italic toggle="yes">Stim1</jats:italic> of <jats:italic toggle="yes">Stim1</jats:italic>-KI SHRSP into SPwch1.71 by the generation of F1 rats ameliorated stroke susceptibility in SPwch1.71. Gene expression, whole-genome sequencing, and biochemical analyses identified <jats:italic toggle="yes">Art2b</jats:italic>, <jats:italic toggle="yes">Folr1</jats:italic>, and <jats:italic toggle="yes">Pde2a</jats:italic> as possible candidate genes accelerating stroke in SPwch1.71.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusion:</jats:title> <jats:p>The substitution of SHRSP-type <jats:italic toggle="yes">Stim1</jats:italic> to wild-type <jats:italic toggle="yes">Stim1</jats:italic> ameliorated stroke susceptibility in both SHRSP and SPwch1.71, indicating that the nonsense mutation in <jats:italic toggle="yes">Stim1</jats:italic> is causally related to stroke susceptibility in SHRSP.</jats:p> </jats:sec>