Mutations involved in Aicardi-Goutières syndrome implicate SAMHD1 as regulator of the innate immune response

Rice, Gillian I.; Bond, Jacquelyn; Asipu, Aruna; Brunette, Rebecca; Manfield, Iain W.; Carr, Ian; Fuller, Jonathan C.; Jackson, Richard M.; Lamb, Teresa M.; Briggs, Tracy A; Ali, Manir; Gornall, Hannah; Couthard, Lydia R; Aeby, Alec; Attard-Montalto, Simon; Bertini, Enrico; Bodemer, Christine; Brockmann, Knut; Brueton, Louise; Corry, Peter; Desguerre, Isabelle; Fazzi, Elisa; Cazorla, Ángels García; Gener, Blanca; Hamel, B.C.J.; Heiberg, Arvid; Hunter, Matthew F.; Knaap, Marjo S. van der; Kumar, Ram; Lagae, Lieven; Landrieu, P.; Lourenço, Charles Marques; Marom, Daphna; McDermott, Michael F.; Merwe, William van der; Orcesi, Simona; Prendiville, Julie S.; Rasmussen, Magnhild; Shalev, Stavit A.; Soler, Doriette; Shinawi, Marwan; Spiegel, Ronen; Tan, Tiong Yang; Vanderver, Adeline; Wakeling, Emma; Wassmer, Evangeline; Whittaker, Elizabeth; Lebon, Pierre; Stetson, Daniel B.; Bonthron, David T.; Crow, Yanick J.

doi:10.1038/ng.373

Cited by 642 publications

(651 citation statements)

References 30 publications

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“…Germ-line mutations in SAMHD1 have been associated with Aicardi-Goutieres syndrome, a congenital autoimmune disease (23), and more recently SAMHD1 was shown to be an HIV-1 restriction factor operating in nondividing blood cells (24,25). Initially, the restriction function of SAMHD1 was attributed to its dNTPase activity, which was presumed to decrease the intracellular dNTP concentrations to levels incompatible with viral replication (26).…”

mentioning

confidence: 99%

Heterozygous colon cancer-associated mutations of SAMHD1 have functional significance

Rentoft

Lindell

Tran

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

105

155

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Even small variations in dNTP concentrations decrease DNA replication fidelity, and this observation prompted us to analyze genomic cancer data for mutations in enzymes involved in dNTP metabolism. We found that sterile alpha motif and histidine-aspartate domain-containing protein 1 (SAMHD1), a deoxyribonucleoside triphosphate triphosphohydrolase that decreases dNTP pools, is frequently mutated in colon cancers, that these mutations negatively affect SAMHD1 activity, and that several SAMHD1 mutations are found in tumors with defective mismatch repair. We show that minor changes in dNTP pools in combination with inactivated mismatch repair dramatically increase mutation rates. Determination of dNTP pools in mouse embryos revealed that inactivation of one SAMHD1 allele is sufficient to elevate dNTP pools. These observations suggest that heterozygous cancer-associated SAMHD1 mutations increase mutation rates in cancer cells.

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mentioning

confidence: 99%

Heterozygous colon cancer-associated mutations of SAMHD1 have functional significance

Rentoft

Lindell

Tran

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

105

155

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“…This evidence suggests that SAMHD1 may act as a nuclease. Mutations in the SAMHD1 gene have recently been identified as one of five causative agents for a rare genetic condition, Aicardi-Goutières syndrome (7,8), highlighting the presence of different pathogenic mutations in the SAMHD1 gene beyond the Amish population. However, the phenotype reported here is apparently incompatible with Aicardi-Goutières syndrome, which is a type of encephalopathy whose clinical features mimic those of acquired in utero viral infection.…”

Section: Discussionmentioning

confidence: 99%

“…Several lines of evidence implicate SAMHD1 in immune function as it is upregulated in response to viral infections and may have a role in mediating TNF-α proinflammatory responses (10)(11)(12)(13). A more recent study suggests that SAMHD1 may act as a negative regulator of the immunostimulatory DNA response and may have a protective role in preventing self-activation of innate immunity (7). Indeed, many clinical findings in our report, particularly abnormal laboratory findings (e.g., elevated ESR, IgG, neopterin, and TNF-α) in the patients support a particular role for SAMHD1 as an immunomodulator.…”

Section: Discussionmentioning

confidence: 99%

Homozygous mutation in SAMHD1 gene causes cerebral vasculopathy and early onset stroke

Xin

Jones

Puffenberger

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

104

113

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We describe an autosomal recessive condition characterized with cerebral vasculopathy and early onset of stroke in 14 individuals in Old Order Amish. The phenotype of the condition was highly heterogeneous, ranging from severe developmental disability to normal schooling. Cerebral vasculopathy was a major hallmark of the condition with a common theme of multifocal stenoses and aneurysms in large arteries, accompanied by chronic ischemic changes, moyamoya morphology, and evidence of prior acute infarction and hemorrhage. Early signs of the disease included mild intrauterine growth restriction, infantile hypotonia, and irritability, followed by failure to thrive and short stature. Acrocyanosis, Raynaud’s phenomenon, chilblain lesions, low-pitch hoarse voice, glaucoma, migraine headache, and arthritis were frequently observed. The early onset or recurrence of strokes secondary to cerebral vasculopathy seems to always be associated with poor outcomes. The elevated erythrocyte sedimentation rate (ESR), IgG, neopterin, and TNF-α found in these patients suggested an immune disorder. Through genomewide homozygosity mapping, we localized the disease gene to chromosome (Chr) 20q11.22-q12. Candidate gene sequencing identified a homozygous mutation, c.1411–2A > G, in the SAMHD1 gene, being associated with this condition. The mutation appeared at the splice-acceptor site of intron 12, resulted in the skipping of exon 13, and gave rise to an aberrant protein with in-frame deletion of 31 amino acids. Immunoblotting analysis showed lack of mutant SAMHD1 protein expression in affected cell lines. The function of SAMHD1 remains unclear, but the inflammatory vasculopathies of the brain found in the patients with SAMHD1 mutation indicate its important roles in immunoregulation and cerebral vascular hemeostasis.

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“…These comprise the RNASEH2A, RNASEH2B and RNASEH2C proteins of the RNase H2 endonuclease complex (Crow et al , 2006b) as well as TREX1, SAMHD1, ADAR and IFIH1 (Crow et al , 2006a; Rice et al , 2009, 2012, 2014). Heterozygous mutations in the three RNase H2 genes (Günther et al , 2015) and TREX1 (Lee‐Kirsch et al , 2007) are also associated with systemic lupus erythematosus.…”

Section: Introductionmentioning

confidence: 99%

Ribonuclease H2 mutations induce a cGAS/STING‐dependent innate immune response

et al. 2016

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Aicardi–Goutières syndrome (AGS) provides a monogenic model of nucleic acid‐mediated inflammation relevant to the pathogenesis of systemic autoimmunity. Mutations that impair ribonuclease (RNase) H2 enzyme function are the most frequent cause of this autoinflammatory disorder of childhood and are also associated with systemic lupus erythematosus. Reduced processing of either RNA:DNA hybrid or genome‐embedded ribonucleotide substrates is thought to lead to activation of a yet undefined nucleic acid‐sensing pathway. Here, we establish Rnaseh2b A174T/A174T knock‐in mice as a subclinical model of disease, identifying significant interferon‐stimulated gene (ISG) transcript upregulation that recapitulates the ISG signature seen in AGS patients. The inflammatory response is dependent on the nucleic acid sensor cyclic GMP‐AMP synthase (cGAS) and its adaptor STING and is associated with reduced cellular ribonucleotide excision repair activity and increased DNA damage. This suggests that cGAS/STING is a key nucleic acid‐sensing pathway relevant to AGS, providing additional insight into disease pathogenesis relevant to the development of therapeutics for this childhood‐onset interferonopathy and adult systemic autoimmune disorders.

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Mutations involved in Aicardi-Goutières syndrome implicate SAMHD1 as regulator of the innate immune response

Cited by 642 publications

References 30 publications

Heterozygous colon cancer-associated mutations of SAMHD1 have functional significance

Heterozygous colon cancer-associated mutations of SAMHD1 have functional significance

Homozygous mutation in SAMHD1 gene causes cerebral vasculopathy and early onset stroke

Ribonuclease H2 mutations induce a cGAS/STING‐dependent innate immune response

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