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Biomed Res Int. 2015;2015:739586. doi: 10.1155/2015/739586. Epub 2015 Oct 4.

SAMHD1 Gene Mutations Are Associated with Cerebral Large-Artery Atherosclerosis.

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Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing 100050, China ; China National Clinical Research Centre for Neurological Diseases, Centre of Stroke, Beijing Institute for Brain Disorders, Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing 100050, China.
DDC Clinic-Center for Special Needs Children, Middlefield, OH 44062, USA.
Department of Molecular Biology and Microbiology, Case Western Reserve University School of Medicine, Cleveland, OH 44193, USA.
Department of Structural Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 45358, USA.
Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, OH 44193, USA.
DDC Clinic-Center for Special Needs Children, Middlefield, OH 44062, USA ; Department of Pediatrics, Case Western Reserve University Medical School, Cleveland, OH 44193, USA ; Rainbow Babies & Children's Hospital, Cleveland, OH 44193, USA ; Department of Molecular Cardiology, Cleveland Clinic, Cleveland, OH 44195, USA.



To investigate whether one or more SAMHD1 gene mutations are associated with cerebrovascular disease in the general population using a Chinese stroke cohort.


Patients with a Chinese Han background (N = 300) diagnosed with either cerebral large-artery atherosclerosis (LAA, n = 100), cerebral small vessel disease (SVD, n = 100), or other stroke-free neurological disorders (control, n = 100) were recruited. Genomic DNA from the whole blood of each patient was isolated, and direct sequencing of the SAMHD1 gene was performed. Both wild type and mutant SAMHD1 proteins identified from the patients were expressed in E. coli and purified; then their dNTPase activities and ability to form stable tetramers were analysed in vitro.


Three heterozygous mutations, including two missense mutations c.64C>T (P22S) and c.841G>A (p.E281K) and one splice site mutation c.696+2T>A, were identified in the LAA group with a prevalence of 3%. No mutations were found in the patients with SVD or the controls (p = 0.05). The mutant SAMHD1 proteins were functionally impaired in terms of their catalytic activity as a dNTPase and ability to assemble stable tetramers.


Heterozygous SAMHD1 gene mutations might cause genetic predispositions that interact with other risk factors, resulting in increased vulnerability to stroke.

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