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Alternative titles; symbolsDENDRITIC CELL-DERIVED IFNG-INDUCED PROTEIN; DCIPHGNC Approved Gene Symbol: SAMHD1Cytogenetic location: 20q11.23 Genomic coordinat...

Alternative titles; symbols


HGNC Approved Gene Symbol: SAMHD1

Cytogenetic location: 20q11.23 Genomic coordinates (GRCh38): 20:36,889,772-36,951,707 (from NCBI)

▼ Description
SAMHD1 is a 3-prime exonuclease and deoxynucleotide (dNTP) triphosphohydrolase. It functions as a human immunodeficiency virus (HIV)-1 (see 609423) restriction factor by hydrolyzing dNTPs and decreasing their concentration to a level below that necessary for retroviral reverse transcription (Behrendt et al., 2013).

▼ Cloning and Expression
Dendritic cells (DCs) are the most potent antigen-presenting cells (APCs) able to induce a primary T-cell response in vivo. With maturation, DCs shift from antigen-uptake and -processing functions to an antigen-presentation phenotype. By screening an EST database derived from a DC cDNA library for sequences homologous to the mouse gamma-interferon (IFNG; 147570)-induced gene Mg11, followed by RACE, Li et al. (2000) obtained a cDNA encoding SAMHD1, which they termed DCIP. The deduced 626-amino acid protein, which is 72% identical to mouse Mg11, contains several phosphorylation and N-myristoylation sites, an N-glycosylation site, and an amidation site. It has no signal peptide or transmembrane region, suggesting that DCIP is an intracellular protein. RT-PCR analysis detected wide but variable expression in most cell lines tested. Northern blot analysis revealed expression of a 5.2-kb transcript in all tissues tested except brain and thymus.

Lahouassa et al. (2012) noted that SAMHD1 consists of an N-terminal sterile alpha motif domain and a central HD domain with putative nucleotidase and phosphodiesterase activities, respectively. They stated that dendritic cells, monocyte-derived macrophages, and HIV-1-permissive CD4 (186940)-positive T cells have high, moderate, and low SAMHD1 expression, respectively.

▼ Mapping
Gross (2012) mapped the SAMHD1 gene to chromosome 20q11.23 based on an alignment of the SAMHD1 sequence (GenBank AB013847) with the genomic sequence (GRCh37).

▼ Gene Function
In Myd88 (602170)-null mice that have impaired immune response, Rice et al. (2009) showed that transfection of macrophages with immunostimulatory DNA resulted in upregulation of Samhd1 expression. Macrophages from Myd88/Ifnar1 (107450) double-knockout mice showed that this expression was interferon-dependent. The findings were consistent with the hypothesis that SAMHD1 expression can be induced by type 1 interferons and suggested that SAMHD1 may also act as a negative regulator of the immunostimulatory DNA response.

Laguette et al. (2011) identified SAMHD1 as the restriction factor that renders human dendritic and myeloid cells largely refractory to HIV-1 infection. SAMHD1 is a protein involved in Aicardi-Goutieres syndrome (see 612952), a genetic encephalopathy with symptoms mimicking congenital viral infection, that has been proposed to act as a negative regulator of the interferon response. Laguette et al. (2011) showed that Vpx, the primate lentivirus auxiliary protein, induces proteasomal degradation of SAMHD1. Silencing of SAMHD1 in nonpermissive cell lines alleviated HIV-1 restriction and was associated with a significant accumulation of viral DNA in infected cells. Concurrently, overexpression of SAMHD1 in sensitive cells inhibited HIV-1 infection. The putative phosphohydrolase activity of SAMHD1 is probably required for HIV-1 restriction. Vpx-mediated relief of restriction was abolished in SAMHD1-negative cells. Finally, silencing of SAMHD1 markedly increased the susceptibility of monocytic-derived dendritic cells to infection. Laguette et al. (2011) concluded that SAMHD1 is an antiretroviral protein expressed in cells of the myeloid lineage that inhibits an early step of the viral life cycle.

Hrecka et al. (2011) independently demonstrated that the inhibition of HIV-1 infection in macrophages involves the cellular SAMHD1 protein. Vpx relieves the inhibition of lentivirus infection in macrophages by loading SAMHD1 onto the CRL4(DCAF1) E3 ubiquitin ligase (see 617259), leading to highly efficient proteasome-dependent degradation of the protein. Mutations in SAMHD1 cause Aicardi-Goutieres syndrome, a disease that produces a phenotype that mimics the effects of a congenital viral infection. Failure to dispose of endogenous nucleic acid debris in Aicardi-Goutieres syndrome results in inappropriate triggering of innate immune responses via cytosolic nucleic acids sensors. Hrecka et al. (2011) concluded that their findings showed that macrophages are defended from HIV-1 infection by a mechanism that prevents an unwanted interferon response triggered by self nucleic acids, and uncovered an intricate relationship between innate immune mechanisms that control response to self and to retroviral pathogens.

Goldstone et al. (2011) showed that human SAMHD1 is a potent dGTP-stimulated triphosphohydrolase that converts deoxynucleoside triphosphates to the constituent deoxynucleoside and inorganic triphosphate. Based on these findings and analysis of the crystal structure of the catalytic core of SAMHD1, Goldstone et al. (2011) proposed that SAMHD1, which is highly expressed in dendritic cells, restricts HIV-1 replication by hydrolyzing the majority of cellular dNTPs, thus inhibiting reverse transcription and viral cDNA synthesis.

By measuring intracellular dNTP pools in human myeloid cells, Lahouassa et al. (2012) found that SAMHD1 lowered the dNTP concentration to an amount that failed to support reverse transcription, thereby establishing a cellular state that was not permissive to lentiviral infection. Vpx induced degradation of SAMHD1, resulting in a large intracellular dNTP pool and restoration of permissiveness to infection. Lahouassa et al. (2012) proposed that nucleotide pool depletion may be a general mechanism for protecting cells from infectious agents that replicate through a DNA intermediate.

Coquel et al. (2018) demonstrated that SAMHD1 promotes degradation of nascent DNA at stalled replication forks in human cell lines by stimulating the exonuclease activity of MRE11 (600814). This function activates the ATR (601215)-CHK1 (603078) checkpoint and allows the forks to restart replication. In SAMHD1-depleted cells, single-stranded DNA fragments are released from stalled forks and accumulate in the cytosol, where they activate the cGAS (613973)-STING (612374) pathway to induce expression of proinflammatory type I interferons (e.g., IFNA1, 147660). Coquel et al. (2018) concluded that SAMHD1 is an important player in the replication stress response, which prevents chronic inflammation by limiting the release of single-stranded DNA from stalled replication forks.

▼ Biochemical Features
Crystal Structure

Goldstone et al. (2011) solved the crystal structure of the catalytic core of SAMHD1, which revealed that the protein is dimeric and indicated a molecular basis for dGTP stimulation of catalytic activity against dNTPs.

▼ Molecular Genetics
Aicardi-Goutieres Syndrome 5

By genomewide linkage analysis and candidate gene sequencing of multiple families with Aicardi-Goutieres syndrome (AGS5; 612952), Rice et al. (2009) identified homozygous or compound heterozygous mutations in the SAMHD1 gene (see, e.g., 606754.0001-606754.0007). Several of the families were consanguineous. All of the mutations involved highly conserved residues, segregated with the disease, and all unaffected parents tested were heterozygous for the mutations.

Chilblain Lupus 2

In a mother and son with chilblain lupus (CHBL2; 614415), Ravenscroft et al. (2011) identified a heterozygous mutation in the SAMHD1 gene (I201N; 606754.0011). The findings suggested that SAMHD1 is involved in innate immunity and inflammation.

▼ Evolution
Laguette et al. (2012) reiterated that while pandemic HIV-1 has no means to counteract SAMHD1 restriction, nonpandemic HIV-2 and certain simian immunodeficiency virus (SIV) strains encode the auxiliary protein Vpx that potently overcomes the block to viral replication constituted by SAMHD1 by promoting its degradation by the proteasome machinery. Evolutionary analysis by Laguette et al. (2012) showed that SAMHD1 experienced strong positive selection episodes during primate evolution. Identification of SAMHD1 residues under positive selection allowed mapping of the Vpx interaction domain of SAMHD1 to the C-terminal region. SAMHD1 proteins of apes, monkeys, and lemurs were all active against HIV-1, whereas Vpx degraded and antagonized SAMHD1 in a species-specific manner. Laguette et al. (2012) questioned whether the presence of Vpx represents an advantage favoring cross-species transmission and observed that Vpx appears to be dispensable for persistence and spread in humans.

Lim et al. (2012) noted that only 2 of 8 primate lentivirus lineages encode Vpx, whereas its paralog, Vpr, is conserved across all extant primate lentiviruses. By functional analysis, they found that multiple Vpx proteins shared the ability to degrade SAMHD1, but that this ability was often host specific. Additionally, some Vpr proteins from viruses lacking Vpx could also potently degrade SAMHD1. Evolutionary analysis showed that the ability to degrade SAMHD1 resulted from neofunctionalization of Vpr that preceded the acquisition of Vpx in primate lentiviruses. Lim et al. (2012) concluded that Vpr gained a new function to degrade SAMHD1 once during viral evolution, thereby initiating an evolutionary 'arms race' with SAMHD1. However, they noted that many lentiviral lineages, including the precursors of HIV-1, never acquired this function.

▼ Animal Model
By generating mice lacking Samhd1, Behrendt et al. (2013) showed that mouse Samhd1 reduced cellular dNTP concentrations and restricted retroviral reverse transcription in lymphocytes, macrophages, and dendritic cells. Absence of Samhd1 triggered Ifnb (IFNB1; 147640)-dependent transcriptional upregulation of type I IFN-inducible genes in various cell types. Behrendt et al. (2013) proposed that Samhd1-deficient mice model important features associated with pathogenic type I IFN responses involved in AGS and SLE pathogenesis.

Independently, Rehwinkel et al. (2013) generated Samhd1 -/- mice and found that they did not develop autoimmune disease, despite displaying a type I IFN signature in spleen, macrophages, and fibroblasts. Cells lacking Samhd1 had elevated dNTP levels, but the deficiency did not lead to increased infection with pseudotyped HIV-1 vectors, likely due to high concentrations of dNTPs in Samhd1 -/- cells. A mutant HIV-1 vector having a reverse transcriptase with reduced affinity for dNTPs was sensitive to Samhd1-dependent restriction in cultured cells and mice. Rehwinkel et al. (2013) concluded that SAMHD1 can restrict lentiviruses in vivo and that nucleotide starvation is an evolutionarily conserved antiviral mechanism. They suggested that HIV-1 may have evolved with a polymerase active at low dNTP concentrations to circumvent SAMHD1 restriction.

▼ ALLELIC VARIANTS ( 11 Selected Examples):

In affected members of a Hungarian family with Aicardi-Goutieres syndrome-5 (AGS5; 612952), Rice et al. (2009) identified a homozygous 625G-A transition in exon 5 of the SAMHD1 gene, resulting in a gly209-to-ser (G209S) substitution at a highly conserved residue. The parents were third cousins. One of the patients died at age 5 years.

In affected members of 2 unrelated families of Maltese origin with Aicardi-Goutieres syndrome-5 (AGS5; 612952), Rice et al. (2009) identified a homozygous 433C-T transition in exon 4 of the SAMHD1 gene, resulting in arg145-to-ter (R145X) substitution at a highly conserved residue.

In 2 sibs with variable manifestations of AGS5, Dale et al. (2010) identified compound heterozygosity for 2 mutations in the SAMHD1 gene: the R145X mutation and a 490C-T transition in exon 4, resulting in an arg164-to-ter (R164X; 606754.0008) substitution. The father was of Maltese origin, and both the father and paternal grandfather reportedly had mild skin involvement, but genetic studies were not performed.

SAMHD1, IVS14AS, G-C, -1
In a Pakistani patient with Aicardi-Goutieres syndrome-5 (AGS5; 612952), Rice et al. (2009) identified a homozygous G-to-C transversion in intron 14 of the SAMHD1 gene (1609-1G-C), resulting in a splice site mutation and the skipping of exon 15 as well as other abnormal transcripts. The parents were related as first cousins.

In affected members of a consanguineous Indian family with Aicardi-Goutieres syndrome-5 (AGS5; 612952), Rice et al. (2009) identified a homozygous 445C-T transition in exon 4 of the SAMHD1 gene, resulting in a gln149-to-ter (Q149X) substitution. Patient cells carrying the Q149X substitution showed localization of the mutant SAMHD1 protein to the nucleus, confirming that the derived mRNA is not subject to nonsense-mediated decay, and indicating that the first 149 amino acids of the protein are sufficient for nuclear localization. However, expression was diminished compared to wildtype and proper localization to internal nuclear structures was less clear.

In a French patient with Aicardi-Goutieres syndrome-5 (AGS5; 612952), Rice et al. (2009) identified a homozygous 1642C-T transition in exon 15 of the SAMHD1 gene, resulting in a gln548-to-ter (Q548X) substitution.

In 2 French sibs with Aicardi-Goutieres syndrome-5 (AGS5; 612952), Rice et al. (2009) identified a compound heterozygosity for a 368A-C transversion in exon 4 of the SAMHD1 gene, resulting in a his123-to-pro (H123P) substitution, and a 760A-G transition in exon 7, resulting in a met254-to-val (M254V; 606754.0007) substitution.

For discussion of the met254-to-val (M254V) mutation in the SAMHD1 gene that was found in compound heterozygous state in 2 sibs with Aicardi-Goutieres syndrome-5 (AGS5; 612952) by Rice et al. (2009), see 606754.0006.

For discussion of the arg164-to-ter (R164X) mutation in the SAMHD1 gene that was found in compound heterozygous state in 2 sibs with variable manifestations of Aicardi-Goutieres syndrome-5 (AGS5; 612952) by Dale et al. (2010), see 606754.0002.

In a boy, born of unrelated Ashkenazi Jewish parents, with severe Aicardi-Goutieres syndrome-5 (AGS5; 612952) including mitochondrial DNA deletions, Leshinsky-Silver et al. (2011) identified a homozygous 9.1-kb deletion involving the SAMHD1 gene. The deletion started upstream of the promoter, encompassed exon 1, and ended in intron 1. The deletion also included the 3-prime end of RBL1 (116957), which may have contributed to the severe phenotype. The parents were each heterozygous for the 9.1-kb deletion, which was not identified in 100 Ashkenazi Jewish controls. The patient presented at age 3 weeks with failure to thrive, poor growth, and lack of development. He had central hypotonia with brisk tendon reflexes and choreoathetoid movements. Brain MRI showed extensive white matter destruction, delayed myelination, hypoplasia of the corpus callosum, severe cortical atrophy, destructive lesions of the aqueductal body and pons, and pathologic lesions in the frontal lobe and basal ganglia. Blood samples showed increased serum lactate, anemia, and thrombocytosis. He had profound mental retardation, poor growth, and severe irritability, and died at age 15 months. Two subsequent pregnancies were terminated after studies showed periventricular white matter lesions and hyperechogenic foci in the basal ganglia between 28 and 34 weeks' gestation. Southern blot analysis of patient skeletal muscle and liver tissue showed multiple mitochondrial DNA deletions, which were not found in blood and fibroblasts, and there were similar findings in fetal autopsy tissues. Leshinsky-Silver et al. (2011) suggested that mutant SAMHD1 causes an induction of the cell intrinsic antiviral response, apoptosis, and mitochondrial DNA destruction.

In a Canadian family with Aicardi-Goutieres syndrome-5 (AGS5; 612952), Rice et al. (2009) identified compound heterozygosity for 2 mutations in the SAMHD1 gene: a 427C-T transition in exon 4, resulting in an arg143-to-cys (R143C) substitution, and a 602T-A transversion in exon 5, resulting in an ile201-to-asn (I201N; 606754.0011) substitution. Both mutations occurred at highly conserved residues.

Aicardi-Goutieres Syndrome 5

For discussion of the ile201-to-asn (I201N) mutation in the SAMHD1 gene that was found in compound heterozygous state in affected individuals from a family with Aicardi-Goutieres syndrome-5 (AGS5; 612952) by Rice et al. (2009), see 606754.0010.

Chilblain Lupus 2

In a mother and son with familial chilblain lupus-2 (CHBL2; 614415), Ravenscroft et al. (2011) identified a heterozygous 602T-A transversion in exon 5 of the SAMHD1 gene, resulting in an I201N substitution at a highly conserved residue. The mutation was not found in 450 control alleles. In early childhood, both patients developed recurrent lesions affecting the hands and feet, as well as variable other regions, particularly over the winter months. Both also had sun sensitivity and later developed angiomatous lesions on the fingers, which became persistent. Biopsy of chilblain skin in the mother showed a florid lymphocytic vasculitis, with papillary dermal edema, interface dermatitis, and keratinocyte necrosis, consistent with lupus. The findings pointed to a defect in innate immunity and inflammation.

Crow et al. (2015) stated that they had identified the I201N mutation in 1 family with chilblain lupus but provided no additional information. It was unclear whether this was the same family reported by Ravenscroft et al. (2011).

Tags: 20q11.23