Characterization of human disease phenotypes associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR, and IFIH1

Abstract

Aicardi–Goutières syndrome is an inflammatory disease occurring due to mutations in any of TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR or IFIH1. We report on 374 patients from 299 families with mutations in these seven genes. Most patients conformed to one of two fairly stereotyped clinical profiles; either exhibiting an in utero disease-onset (74 patients; 22.8% of all patients where data were available), or a post-natal presentation, usually within the first year of life (223 patients; 68.6%), characterized by a sub-acute encephalopathy and a loss of previously acquired skills. Other clinically distinct phenotypes were also observed; particularly, bilateral striatal necrosis (13 patients; 3.6%) and non-syndromic spastic paraparesis (12 patients; 3.4%). We recorded 69 deaths (19.3% of patients with follow-up data). Of 285 patients for whom data were available, 210 (73.7%) were profoundly disabled, with no useful motor, speech and intellectual function. Chilblains, glaucoma, hypothyroidism, cardiomyopathy, intracerebral vasculitis, peripheral neuropathy, bowel inflammation and systemic lupus erythematosus were seen frequently enough to be confirmed as real associations with the Aicardi-Goutieres syndrome phenotype. We observed a robust relationship between mutations in all seven genes with increased type I interferon activity in cerebrospinal fluid and serum, and the increased expression of interferon-stimulated gene transcripts in peripheral blood. We recorded a positive correlation between the level of cerebrospinal fluid interferon activity assayed within one year of disease presentation and the degree of subsequent disability. Interferon-stimulated gene transcripts remained high in most patients, indicating an ongoing disease process. On the basis of substantial morbidity and mortality, our data highlight the urgent need to define coherent treatment strategies for the phenotypes associated with mutations in the Aicardi–Goutières syndrome-related genes. Our findings also make it clear that a window of therapeutic opportunity exists relevant to the majority of affected patients and indicate that the assessment of type I interferon activity might serve as a useful biomarker in future clinical trials.

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

“…Full pathological examination of brain, liver, heart, lungs, thymus, spleen, gastrointestinal tract, kidneys, skin and tongue from mice ( n  = 9) did not detect histological features of inflammation, infection or neoplasia at 1 year (data not shown). In particular, there was no evidence of intracranial calcification, leukodystrophy, chilblain vasculitis or cardiomyopathy, clinical features associated with AGS in humans (Crow et al , 2015). Notably, histopathological signs of inflammation are also not evident in Samhd1 −/− mice, although activation of innate immune signalling does occur, with ISG upregulation evident (Behrendt et al , 2013; Rehwinkel et al , 2013).…”

“…In contrast a strong ISG response in Adar1 null or editing‐deficient mice is associated with embryonic lethality (Mannion et al , 2014; Liddicoat et al , 2015; Pestal et al , 2015), and with autoinflammatory cardiomyopathy and multi‐tissue involvement in Trex1 −/− mice (Morita et al , 2004; Stetson et al , 2008; Gall et al , 2012). The variation in severity between different AGS gene mouse models remains unexplained, although it may be meaningful that mutations in human RNASEH2B are associated with the least severe disease course, with AGS onset generally in infancy, in contrast to the prenatal/neonatal onset more commonly seen in TREX1 patients (Crow et al , 2015). Also, additional triggers, such as viral infection, have been proposed to be relevant to the pathogenesis of AGS (Crow & Manel, 2015).…”

“…AGS typically presents in infancy following a period of normal development, with sterile pyrexia, irritability, seizures and loss of developmental milestones (Crow & Livingston, 2008). Persisting severe physical and intellectual disability is frequent, and extra‐neurological features can include vasculitic skin lesions (Crow & Livingston, 2008; Crow et al , 2015). Increased type 1 interferon activity is most reliably detected during the early stages of the disease (Crow et al , 2015).…”

“…Persisting severe physical and intellectual disability is frequent, and extra‐neurological features can include vasculitic skin lesions (Crow & Livingston, 2008; Crow et al , 2015). Increased type 1 interferon activity is most reliably detected during the early stages of the disease (Crow et al , 2015). However, upregulated interferon‐stimulated gene (ISG) transcripts in blood have proven to be the most robust diagnostic biomarker in AGS patients, and an “ISG signature” often persists long after the initial stages of disease (Rice et al , 2013; Crow et al , 2015).…”

“…Partial loss‐of‐function biallelic mutations in the RNase H2 genes are the major cause of AGS, accounting for over half of all cases (Crow et al , 2015). RNase H2 is ubiquitously expressed and functions alongside RNase H1 to degrade cellular RNA:DNA heteroduplexes.…”