SAMHD1 Gene Mutations Are Associated with Cerebral Large-Artery Atherosclerosis.
BACKGROUND
To investigate whether one or more SAMHD1 gene mutations are associated with cerebrovascular disease in the general population using a Chinese stroke cohort.


METHODS
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.


RESULTS
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.


CONCLUSIONS
Heterozygous SAMHD1 gene mutations might cause genetic predispositions that interact with other risk factors, resulting in increased vulnerability to stroke.
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.
Wei
W
Li
DDC Clinic-Center for Special Needs Children, Middlefield, OH 44062, USA.
Baozhong
B
Xin
Department of Molecular Biology and Microbiology, Case Western Reserve University School of Medicine, Cleveland, OH 44193, USA.
Junpeng
J
Yan
Department of Structural Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 45358, USA.
Ying
Y
Wu
Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, OH 44193, USA.
Bo
B
Hu
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.
Liping
L
Liu
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.
Yilong
Y
Wang
Department of Structural Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 45358, USA.
Jinwoo
J
Ahn
Department of Molecular Biology and Microbiology, Case Western Reserve University School of Medicine, Cleveland, OH 44193, USA.
Jacek
J
Skowronski
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.
Zaiqiang
Z
Zhang
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.
Yongjun
Y
Wang
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.
Heng
H
Wang
D000368:Aged; D044466:Asian People / Q000235:genetics; D050197:Atherosclerosis / Q000453:epidemiology / Q000235:genetics*; D002536:Cerebral Arteries / Q000000981:diagnostic imaging; D002681:China / Q000453:epidemiology; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005260:Female; D020022:Genetic Predisposition to Disease / Q000453:epidemiology / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D011859:Radiography; D000076106:SAM Domain and HD Domain-Containing Protein 1; D020521:Stroke / Q000453:epidemiology / Q000235:genetics*
D000076106:SAM Domain and HD Domain-Containing Protein 1; C484280:SAMHD1 protein, human; D020559:Monomeric GTP-Binding Proteins