SAMHD1 – Aicardi-Goutières Syndrome 5

Sterile alpha motif and HD domain-containing protein 1 (SAMHD1) is a dNTP triphosphohydrolase that regulates intracellular deoxynucleotide pools and innate immune signaling. Biallelic loss-of-function variants in SAMHD1 cause Aicardi-Goutières syndrome 5 (AGS5), an autosomal recessive type I interferonopathy presenting with encephalopathy and white matter abnormalities.

A first Polish patient with AGS5 presented with deep temporal lobe white matter cysts and leukodystrophy confirming AR inheritance. Whole-exome sequencing revealed compound heterozygous missense and truncating variants p.Phe165Ser/p.Gln235Ter (PMID:35418820). Segregation was consistent with affected siblings unavailable for testing.

The variant spectrum in AGS5 includes nonsense, frameshift, splice, and missense mutations clustering in the HD domain. The truncating variant c.703C>T (p.Gln235Ter) abolishes catalytic activity and is predicted to undergo nonsense-mediated decay (PMID:35418820).

Functional studies of AGS-associated SAMHD1 mutants demonstrate disrupted nucleic-acid binding and mislocalization to the cytosol. Truncating and missense variants across the HD domain fail to bind RNA and accumulate in the cytoplasm, leading to constitutive type I interferon activation in patient cells (PMID:22461318).

Cellular models show that loss of nuclear localization and HD-domain integrity impairs dNTPase function and drives STING-dependent interferon signaling. Rescue experiments with wild-type SAMHD1 restore nuclear localization, normalize dNTP levels, and suppress interferon-stimulated gene expression, confirming a loss-of-function mechanism (PMID:22461318).

Collectively, autosomal recessive SAMHD1 mutations are causative for AGS5; genetic testing enables definitive diagnosis, guides interferon-modulating therapies, and informs genetic counseling. Early identification of SAMHD1 variants is critical for clinical decision-making in suspected interferonopathies.

References

• Molecular syndromology • 2022 • Aicardi-Goutières Syndrome due to a SAMHD1 Mutation Presenting with Deep White Matter Cysts PMID:35418820
• Human Mutation • 2012 • SAMHD1 is a nucleic-acid binding protein that is mislocalized due to aicardi-goutières syndrome-associated mutations PMID:22461318

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