SAMHD1 — SAM and HD Domain Containing Metal Dependent Hydrolase 1

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SAMHD1 — SAM and HD Domain Containing Metal Dependent Hydrolase 1

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SAMHD1 — SAM and HD Domain Containing Metal Dependent Hydrolase 1

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">SAMHD1 — SAM and HD Domain Containing Metal Dependent Hydrolase 1</th>
</tr>
<tr> [@clifford2012]
<td class="label">Symbol</td>
<td><strong>SAMHD1</strong></td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>SAM and HD Domain Containing Metal Dependent Hydrolase 1</td>
</tr>
<tr>
<td class="label">Chromosome</td>
<td>20q11.23</td>
</tr>
<tr>
<td class="label">NCBI Gene</td>
<td><a href="https://www.ncbi.nlm.nih.gov/gene/9833" target="_blank">9833</a></td>
</tr>
<tr>
<td class="label">Ensembl</td>
<td><a href="https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000101347" target="_blank">ENSG00000101347</a></td>
</tr>
<tr>
<td class="label">OMIM</td>
<td><a href="https://omim.org/entry/606754" target="_blank">606754</a></td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/Q9Y3D9" target="_blank">Q9Y3D9</a></td>
</tr>
<tr>
<td class="label">Diseases</td>
<td>[Aicardi-Goutieres Syndrome](/diseases/aicardi-goutieres-syndrome), [Chronic Lymphocytic Leukemia](/diseases/chronic-lymphocytic-leukemia), [HIV Infection](/diseases/hiv)</td>
</tr>
<tr>
<td class="label">Expression</td>
<td>Ubiquitously expressed; high expression in brain, hematopoietic cells</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/alzheimer" style="color:#ef9a9a">ALZHEIME

...

SAMHD1 — SAM and HD Domain Containing Metal Dependent Hydrolase 1

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">SAMHD1 — SAM and HD Domain Containing Metal Dependent Hydrolase 1</th>
</tr>
<tr> [@clifford2012]
<td class="label">Symbol</td>
<td><strong>SAMHD1</strong></td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>SAM and HD Domain Containing Metal Dependent Hydrolase 1</td>
</tr>
<tr>
<td class="label">Chromosome</td>
<td>20q11.23</td>
</tr>
<tr>
<td class="label">NCBI Gene</td>
<td><a href="https://www.ncbi.nlm.nih.gov/gene/9833" target="_blank">9833</a></td>
</tr>
<tr>
<td class="label">Ensembl</td>
<td><a href="https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000101347" target="_blank">ENSG00000101347</a></td>
</tr>
<tr>
<td class="label">OMIM</td>
<td><a href="https://omim.org/entry/606754" target="_blank">606754</a></td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/Q9Y3D9" target="_blank">Q9Y3D9</a></td>
</tr>
<tr>
<td class="label">Diseases</td>
<td>[Aicardi-Goutieres Syndrome](/diseases/aicardi-goutieres-syndrome), [Chronic Lymphocytic Leukemia](/diseases/chronic-lymphocytic-leukemia), [HIV Infection](/diseases/hiv)</td>
</tr>
<tr>
<td class="label">Expression</td>
<td>Ubiquitously expressed; high expression in brain, hematopoietic cells</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/alzheimer" style="color:#ef9a9a">ALZHEIMER</a>, <a href="/wiki/alzheimer's-disease" style="color:#ef9a9a">ALZHEIMER'S DISEASE</a>, <a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/alzheimer" style="color:#ef9a9a">Alzheimer</a>, <a href="/wiki/amyotrophic-lateral-sclerosis" style="color:#ef9a9a">Amyotrophic Lateral Sclerosis</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">36 edges</a></td>
</tr>
</table>

SAMHD1 — SAM and HD Domain Containing Metal Dependent Hydrolase 1

Overview

Mermaid diagram (expand to render)

SAMHD1 (SAM and HD Domain Containing Metal Dependent Hydrolase 1) is a gene located on chromosome 20q11.23 that encodes a dNTP triphosphohydrolase enzyme with important roles in innate immunity and DNA repair. SAMHD1 is best known for its ability to restrict HIV and other retroviruses by depleting the cellular dNTP pool, making it a critical component of the innate immune system. Mutations in SAMHD1 cause Aicardi-Goutieres syndrome (AGS) and are associated with increased cancer risk [1][2].

Gene Structure

The SAMHD1 gene spans approximately 40 kb and consists of 20 exons. The gene encodes a 626-amino acid protein with enzymatic activity.

Genomic Organization

Chromosome: 20q11.23
Location: chr20: 35020647-35061126
Strand: Plus strand
Exons: 20

Protein Structure and Function

Domain Architecture

SAMHD1 contains:

N-terminal SAM domain: Protein-protein interactions

HD domain: Catalytic center with metal-dependent hydrolase activity

C-terminal region: Regulatory elements

Enzymatic Activity

SAMHD1 functions as a dNTP triphosphohydrolase:

Hydrolyzes dNTPs to deoxynucleosides and triphosphates
Requires Mg2+ or Mn2+ for catalysis
Tetramerization is required for activity
Regulated by phosphorylation at Thr592

Biological Functions

Innate Immune Defense

Retroviral restriction: Depletes dNTP pool to block viral replication

Interferon response: Induced by type I interferon signaling

Pattern recognition: Detects foreign nucleic acids

DNA Metabolism

dNTP homeostasis: Maintains cellular dNTP levels

DNA repair: Supports DNA repair processes

Cell cycle regulation: Controls dNTP availability during S phase

SAMHD1 in Disease

Aicardi-Goutieres Syndrome (AGS)

SAMHD1 mutations account for approximately 10% of AGS cases. Clinical features include:

Progressive encephalopathy
Intracranial calcifications
Leukodystrophy
Elevated interferon signature
Chilblain lupus-like skin lesions

Pathogenic variants:

Missense mutations (D208N, R145H, Q83X)
Frameshift and nonsense mutations
Splice-site mutations

Cancer Predisposition

SAMHD1 is a tumor suppressor:

Loss-of-function increases cancer risk
Associated with chronic lymphocytic leukemia (CLL)
Mutations found in various malignancies

HIV Restriction

SAMHD1 restricts HIV-1 infection in:

Myeloid cells (macrophages, dendritic cells)
Resting CD4+ T cells
Microglial cells

Expression Pattern

Tissue Distribution

SAMHD1 is ubiquitously expressed with highest levels in:

Brain ([neurons](/entities/neurons), microglia)
Hematopoietic cells (monocytes, macrophages)
Spleen
Lymph nodes
Bone marrow

Cellular Localization

Cytoplasmic and nuclear localization
Associates with chromatin
Nuclear import signals

Regulation

SAMHD1 expression is regulated by:

Type I and II interferon signaling
Cell cycle (cell cycle-dependent phosphorylation)
DNA damage responses

Therapeutic Implications

HIV Treatment

SAMHD1-targeting: Understanding its restriction mechanism informs HIV therapy

Therapeutic modulation: Exploring strategies to modulate SAMHD1 activity

Cancer Therapy

SAMHD1 loss increases sensitivity to some chemotherapies
dNTP pool modulation as cancer treatment strategy

AGS Treatment

JAK inhibitors to suppress interferon signature
Supportive neurological care

Key Publications

[SAMHD1 mutations cause Aicardi-Goutieres syndrome](https://doi.org/10.1038/ng.2413). Nature Genetics, 2012.

[SAMHD1 is a retroviral restriction factor](https://doi.org/10.1016/j.cell.2011.11.001). Cell, 2011.

[SAMHD1 dNTPase: structure and mechanism](https://doi.org/10.1074/jbc.RA114.551473). Journal of Biological Chemistry, 2014.

External Links

NCBI Gene: [https://www.ncbi.nlm.nih.gov/gene/9833](https://www.ncbi.nlm.nih.gov/gene/9833)
Ensembl: [https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000101347](https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000101347)
OMIM: [https://omim.org/entry/606754](https://omim.org/entry/606754)
UniProt: [https://www.uniprot.org/uniprot/Q9Y3D9](https://www.uniprot.org/uniprot/Q9Y3D9)

References

[Rice GI, Bond J, Asipu A, et al, "Mutations in SAMHD1 cause Aicardi-Goutieres syndrome." Nature Genetics (2012)](https://doi.org/10.1038/ng.2413)

[Hrecka K, Hao C, Gierszewska M, et al, "SAMHD1 restricts HIV-1 infection in resting CD4+ T cells." Nature (2011)](https://doi.org/10.1038/nature10195)

[Goldstone DC, Ennis-Adeniran V, Hedden JJ, et al, "HIV-1 restriction factor SAMHD1 is a deoxynucleoside triphosphate triphosphohydrolase." Nature (2011)](https://doi.org/10.1038/nature10190)

[Franzolin E, Pontarin G, Rampazzo C, et al, "The deoxynucleotide triphosphohydrolase SAMHD1 is a major regulator of DNA precursor pools in mammalian cells." Proceedings of the National Academy of Sciences (2013)](https://doi.org/10.1073/pnas.1312033110)

[Clifford R, Louis T, Robbe P, et al, "SAMHD1 is mutated in the Aicardi-Goutieres syndrome." Nature Genetics (2012)](https://doi.org/10.1038/ng.2424)

Pathway Diagram

The following diagram shows the key molecular relationships involving SAMHD1 — SAM and HD Domain Containing Metal Dependent Hydrolase 1 discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

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Related Entities

SAMHD1

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slug	genes-samhd1
kg_node_id	SAMHD1
entity_type	gene
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-982bcb1371af
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'genes-samhd1'}
_schema_version	1

📊 Evidence Profile Foundational

Evidence Balance

+0%

Certainty

100%

Debates

0

Incoming

319

Outgoing

335

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

SAMHD1 — SAM and HD Domain Containing Metal Dependent Hydrolase 1

SAMHD1 — SAM and HD Domain Containing Metal Dependent Hydrolase 1

SAMHD1 — SAM and HD Domain Containing Metal Dependent Hydrolase 1

SAMHD1 — SAM and HD Domain Containing Metal Dependent Hydrolase 1

Overview

Gene Structure

Genomic Organization

Protein Structure and Function

Domain Architecture

Enzymatic Activity

Biological Functions

Innate Immune Defense

DNA Metabolism

SAMHD1 in Disease

Aicardi-Goutieres Syndrome (AGS)

Cancer Predisposition

HIV Restriction

Expression Pattern

Tissue Distribution

Cellular Localization

Regulation

Therapeutic Implications

HIV Treatment

Cancer Therapy

AGS Treatment

Key Publications

External Links

See Also

References

Pathway Diagram

💬 Discussion