Heterozygous OAS1 gain-of-function variants cause an autoinflammatory immunodeficiency

Abstract

Analysis of autoinflammatory and immunodeficiency disorders elucidates human immunity and fosters the development of targeted therapies. Oligoadenylate synthetase 1 is a type I interferon–induced, intracellular double-stranded RNA (dsRNA) sensor that generates 2′-5′-oligoadenylate to activate ribonuclease L (RNase L) as a means of antiviral defense. We identified four de novo heterozygous OAS1 gain-of-function variants in six patients with a polymorphic autoinflammatory immunodeficiency characterized by recurrent fever, dermatitis, inflammatory bowel disease, pulmonary alveolar proteinosis, and hypogammaglobulinemia. To establish causality, we applied genetic, molecular dynamics simulation, biochemical, and cellular functional analyses in heterologous, autologous, and inducible pluripotent stem cell–derived macrophages and/or monocytes and B cells. We found that upon interferon-induced expression, OAS1 variant proteins displayed dsRNA-independent activity, which resulted in RNase L–mediated RNA cleavage, transcriptomic alteration, translational arrest, and dysfunction and apoptosis of monocytes, macrophages, and B cells. RNase L inhibition with curcumin modulated and allogeneic hematopoietic cell transplantation cured the disorder. Together, these data suggest that human OAS1 is a regulator of interferon-induced hyperinflammatory monocyte, macrophage, and B cell pathophysiology.

A national diagnostic framework for patients with ultra-rare disorders: molecular genetic findings using phenotypic and sequencing data

“…We identi ed a de novo gain-of-function variant that caused dsRNAindependent activity of OAS1 in a patient with immunode ciency, pulmonary alveolar proteinosis, and phospholipid accumulation. The hyperin ammatory disorder was cured by allogeneic hematopoietic cell transplantation 45 . A homozygous frameshift variant in CYHR1, encoding a protein with to-date-unknown function but high cerebral and cerebellar expression, was identi ed in a girl from non-consanguineous parents who presented with global developmental delay and hyperre exia.…”

“…Fifteen genes have subsequently reached DGG status. We brie y describe a few exemplary cases below, most of which have already been published in detail elsewhere [43][44][45][46][47][48][49][50][51][52] , and provide a comprehensive list of all patients in the Supplemental Material. In SMARCA5, a gene coding for a chromatin remodeler, we identi ed de novo variants in two patients with neurodevelopmental delay and similar dysmorphic features.…”

Role of helical structure and dynamics in oligoadenylate synthetase 1 (OAS1) mismatch tolerance and activation by short dsRNAs

“…Although the differences between the dsRNA are relatively small (up to approximately fourfold), sustained activation at such elevated levels during infection would promote significantly faster accumulation of sufficient 2-5A to effect a more rapid cellular response and earlier amplification of downstream antiviral activities. Further, recent evidence shows that even very low levels of persistent 2-5A synthesis from OAS1 gain-of-function activity can have dramatic cellular consequences and lead to devastating human disease ( 43 ). Our insights also provide a basis for better understanding how more complex, structured RNAs may accomplish their strong OAS1 activation.…”

Early‐onset, fatal interstitial lung disease in STAT3 gain‐of‐function patients

“…However, ILD phenotypes have been reported in different inborn errors of immunity (IEI) associated with Treg dysfunction besides STAT3 GOF disease, 2 that is, IL2RB deficiency, 12 CD25 deficiency, 13 IPEX syndrome, 14 CTLA4 haploinsufficiency 15 or LRBA deficiency 16 . In addition, pulmonary involvement is also a prominent feature of monogenic autoinflammatory disorders affecting the regulation of type I interferon signaling, for example, SAVI syndrome, 17 COPA syndrome 18,19 or OAS1 GOF disease 20 . It is therefore mandatory to consider these IEIs in children with ILD onset before the age of 3 years, especially when additional signs of immune dysregulation like eczema or organ‐specific autoimmunity, most evident in the clinical course of case 2, are present.…”

“…16 In addition, pulmonary involvement is also a prominent feature of monogenic autoinflammatory disorders affecting the regulation of type I interferon signaling, for example, SAVI syndrome, 17 COPA syndrome 18,19 or OAS1 GOF disease. 20 It is therefore mandatory to consider these IEIs in children with ILD onset before the age of 3 years, especially when additional signs of immune dysregulation like eczema or organ-specific autoimmunity, most evident in the clinical course of case 2, are present. In addition to standard immune function assays, Treg enumeration and interferon scores appear to be valuable screening tests.…”