SAMHD1 Gene Mutations Are Associated with Cerebral Large-Artery Atherosclerosis

Heng Wang, MD, PhD and Baozhong Xin, PhD, DDC Clinic - Center for Special Needs Children, Middlefield, OH 44062, USA

H. Wang
H. Wang
B. Xin
B. Xin

Background and Hypothesis

Increasing evidence suggests that there is a significant genetic predisposition to cerebrovascular disorders, and these genetic risk factors may account for some portion of the unexplained risk of stroke [1,2]. Identifying these genetic risk factors will not only allow better risk prediction but will also provide valuable insights into the mechanism of disease development. We have previously described a cohort of patients from the Old Order Amish, an inbred population who present a functional loss of the SAMHD1 gene resulting from a homozygous c.1411-2A>G mutation [3]. Although the phenotype of this autosomal recessive condition is heterogeneous, involving multiple systems, the presence of cerebral vasculopathy appears to be a major hallmark of the condition [3,4]. Similar cerebrovascular findings have also been reported in patients with SAMHD1 mutations by other groups [5,6], and we proposed "SAMS (an acronym of cerebrovascular stenosis, aneurysm, moyamoya, and stroke) association" as the name of the disease [4]. As recent studies have revealed that SAMHD1 is a dGTP-regulated deoxyribonucleoside triphosphate triphosphohydrolase (dNTPase) [7,8], and its tetramerization is required for biological activity [9], we speculate that a single mutation in one allele of the SAMHD1 gene may act in a dominant negative manner with the potential to become pathogenic in humans, thus associated with stroke in the general population.

Experimental Designs and Results

To test this hypothesis, we investigated a stroke cohort with a completely different ethnic background from that of the original studies. This present study [10] included 300 patients with a Chinese Han background, diagnosed with either cerebral large-artery atherosclerosis (LAA), cerebral small vessel disease (SVD), or other stroke-free neurological disorders (control) as shown in Table 1. Genomic DNA from the whole blood was isolated, and direct sequencing of the SAMHD1 gene was performed in each patient.  We identified three heterozygous mutations, including two missense mutations c.64C>T (P22S) and c.841G>A (E281K), and one splice site mutation c.696+2T>A in the LAA group with a prevalence of 3%, whereas no mutations were found among 200 patients with SVD or stroke-free controls (p = 0.05). The two missense mutations, P22S and E281K, caused amino acid substitutions located proximal to the conserved SAM domain and in the catalytic core of the enzyme, respectively, while the splice site mutation c.696+2T>A in intron 6 led to a putative aberrant splicing event. None of the three variants has been reported previously or is present in the 1000 Genomes Project database ( In the ExAC database (, and the P22S and E281K missense mutations have only been observed in a frequency of 0.0008% and 0.002%, respectively. It also should be noted that along with SAMHD1 mutations, multiple stroke risk factors, such as hypertension, hyperlipidemia, hyperhomocysteinemia, and alcohol and tobacco use, were also identified in all three patients. Thus, we suggest that SAMHD1 mutations might create a genetic predisposition for stroke that leads to an increased vulnerability to stroke in those patients by interacting with other risk factors.


Table 1. Age and gender distributions among the patients

LAA                SVD               Control

(N = 100)       (N = 100)       (N = 100)


Age (Means ± SD, years)           59.3 ± 9.5      59.8 ± 9.1      62.9 ± 6.3


Gender (Male/Female)                76/24              55/45              50/50


Discussions and Implications

The exact mechanism of how the SAMHD1 mutations serve as a genetic predisposition for stroke remains unclear. However, our functional studies indicated that the missense mutations c.64C>T (P22S) and c.841G>A (E281K) identified in the stroke patients impair the function of the SAMHD1 protein as the catalytic activities of the E281K and P22S mutant was both severely diminished, as predicted by the results of tetramerization assays.  The other mutation, c.696+2T>A, was predicted to produce a SAMHD1 protein with severely truncated catalytic domains, precluding it from being an active dNTPase. Increasing evidence indicates that SAMHD1 may act as an immunomodulator that plays a protective role by preventing the self-activation of innate immunity [11,12]. Our findings here suggest that impaired functions of this protein might result in an unremittingly proinflammatory status in the affected individuals, thus directly or indirectly initiating progression of the pathological process of LAA. Several lines of evidence implicate SAMHD1 in immune function, as it is upregulated in response to viral infections and is thought to play a role in mediating TNF-α proinflammatory responses [13,14]. However, TNF-α is significantly associated with large artery atherosclerosis [15], suggesting that SAMHD1 may initiate the progression of LAA via the TNF-α pathway. Indeed, abnormal laboratory findings, including elevated ESR, immunoglobulin G, neopterin, and TNF-α, have been found in patients with the homozygous mutation [3].

The vast majority of strokes are increasingly recognized as polygenic events. Although monogenic causes of stroke are rare, identification of these genes and mutations is important to provide critical information for the diagnosis, treatment, and prognosis of affected individuals. Furthermore, identifying novel gene variants associated with stroke may reveal novel pathways involved in stroke pathogenesis and thus result in new targeted treatments and more effective prevention of stroke. In this study, although the incidence of SAMHD1 mutations in LAA patients was only 3%, this prevalence is noteworthy in light of the complexity of the multiple genetic and environmental risk factors that influence the disease. We suspect if studies are performed in patient population with early onset of stroke, or stoke patients with additional vasculopathy such as aneurysm and moyamoya, the incidence of SAMHD1 mutations might be higher. Further studies involving additional patient populations, particularly the targeted cohorts as described above, and exploring the mechanism underlying the effect of SAMHD1 mutations on the development of LAA in the general population will be valuable, not only for patients who are directly affected but also for stroke patients in general.


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