Clinical and Molecular Phenotype of Aicardi-Goutières Syndrome

Leeds Institute of Molecular Medicine, St James's University Hospital, Leeds, LS9 7TF, UK.
The American Journal of Human Genetics (Impact Factor: 10.99). 10/2007; 81(4):713-25. DOI: 10.1086/521373
Source: PubMed

ABSTRACT Aicardi-Goutieres syndrome (AGS) is a genetic encephalopathy whose clinical features mimic those of acquired in utero viral infection. AGS exhibits locus heterogeneity, with mutations identified in genes encoding the 3'-->5' exonuclease TREX1 and the three subunits of the RNASEH2 endonuclease complex. To define the molecular spectrum of AGS, we performed mutation screening in patients, from 127 pedigrees, with a clinical diagnosis of the disease. Biallelic mutations in TREX1, RNASEH2A, RNASEH2B, and RNASEH2C were observed in 31, 3, 47, and 18 families, respectively. In five families, we identified an RNASEH2A or RNASEH2B mutation on one allele only. In one child, the disease occurred because of a de novo heterozygous TREX1 mutation. In 22 families, no mutations were found. Null mutations were common in TREX1, although a specific missense mutation was observed frequently in patients from northern Europe. Almost all mutations in RNASEH2A, RNASEH2B, and RNASEH2C were missense. We identified an RNASEH2C founder mutation in 13 Pakistani families. We also collected clinical data from 123 mutation-positive patients. Two clinical presentations could be delineated: an early-onset neonatal form, highly reminiscent of congenital infection seen particularly with TREX1 mutations, and a later-onset presentation, sometimes occurring after several months of normal development and occasionally associated with remarkably preserved neurological function, most frequently due to RNASEH2B mutations. Mortality was correlated with genotype; 34.3% of patients with TREX1, RNASEH2A, and RNASEH2C mutations versus 8.0% RNASEH2B mutation-positive patients were known to have died (P=.001). Our analysis defines the phenotypic spectrum of AGS and suggests a coherent mutation-screening strategy in this heterogeneous disorder. Additionally, our data indicate that at least one further AGS-causing gene remains to be identified.

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Available from: Daniel R Carvalho, Aug 26, 2015
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    • "At the same time, monitoring of genome wide changes induced by the inhibitors, such as microarray and PCR array, is ongoing. Genetic studies of AGS patients have shown that biallelic mutations in RNASEH2A, RNASEH2B, and RNASEH2C were observed in 3, 47, and 18 cases, respectively (Rice et al., 2007). Moreover, of five mutations analyzed in human RNASE2B and RNASE2C linked to AGS, only one, R69W in the RNASEH2C protein, exhibited a significant reduction in specific activity (Chon et al., 2009). "
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    ABSTRACT: A total of 140,000 compounds were screened in a targetfree cell-based high throughput assay against HIV-1 infection, and a subset of 81 promising compounds was identified. Secondary screening of these 81 compounds revealed two putative human RNaseH2 inhibitors, RHI001 and RHI002, with IC50 value of 6.8 μM and 16 μM, respectively. RHI002 showed selective activity against human RNaseH2 while RHI001 inhibited HIV-RNaseH, E. coli RNaseH, and human RNaseH1 with IC50 value of 28.5 μM, 7.9 μM, and 31.7 μM, respectively. Kinetic analysis revealed that both inhibitors had non-competitive inhibitor-like properties. Because RNaseH2 is involved in the etiology of Aicardi-Goutier syndrome and has been suggested as an anticancer drug target, small molecule inhibitors modulating its activity would be useful for investigating the cellular function of this molecule.
    Moleculer Cells 09/2013; 36(3). DOI:10.1007/s10059-013-2348-z · 2.24 Impact Factor
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    • "704G>A (p.Arg235Gln) in patient P1, c.556C>T (p.Arg186Trp) in patient 3, and c.635A>T (p.Asn212Ile) in patient 4 (Coffin, et al., 2011; Rice, et al., 2007 "
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    ABSTRACT: ABSTRACT Aicardi-Goutières syndrome (AGS) is an inflammatory disorder resulting from mutations in TREX1, RNASEH2A/2B/2C, SAMHD1 or ADAR1. Here we provide molecular, biochemical and cellular evidence for the pathogenicity of two synonymous variants in RNASEH2A. Firstly, the c.69G>A (p.Val23Val) mutation causes the formation of a splice donor site within exon 1, resulting in an out of frame deletion at the end of exon 1, leading to reduced RNase H2 protein levels. The second mutation, c.75C>T (p.Arg25Arg), also introduces a splice donor site within exon 1, and the internal deletion of 18 amino acids. The truncated protein still forms a heterotrimeric RNase H2 complex, but lacks catalytic activity. However, as a likely result of leaky splicing, a small amount of full-length active protein is apparently produced in an individual homozygous for this mutation. Recognition of the disease causing status of these variants allows for diagnostic testing in relevant families.
    Human Mutation 08/2013; 34(8). DOI:10.1002/humu.22336 · 5.05 Impact Factor
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    • "Loss of function mutations in the human Trex1 gene cause Aicardi-Goutieres Syndrome (AGS; Crow et al., 2006a). AGS presents in infancy as a severe encephalitis with intracranial calcifications, lymphocyte infiltrates and elevated type I IFN levels in cerebrospinal fluid, and demyelination of motor neurons with accompanying psychomotor retardation (Rice et al., 2007b). Many of these symptoms resemble those caused by congenitally acquired infection with cytomegalovirus or rubella virus (Crow et al., 2003; Sanchis et al., 2005), but no viral pathogen has been detected in AGS patients. "
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