Genetics, Pathophysiology, and Treatment of Recessive Autoinflammatory Diseases

National Human Genome Research Institute

Investigators

Linked publications, trials & patents

Abstract

During the current reporting period we focused on the following projects: 1) Deficiency of adenosine deaminase 2 (DADA2) In a previous reporting period, we published a manuscript in the New England Journal of Medicine demonstrating the efficacy of tumor necrosis factor (TNF) inhibitors in preventing strokes in DADA2. Our current cohort of DADA2 patients is now more than 55 patients, and we continue to observe that TNF inhibitors are highly effective in preventing strokes, although TNF inhibition does not appear to be effective in preventing the hematologic manifestations of DADA2. In collaboration with Peter Merkel and the Vasculitis Clinical Research Consortium, we have screened 117 patients with idiopathic polyarteritis nodosa (PAN), all of whom tested negative for hepatitis B virus infection, for ADA2 mutations. Four (3.4%) had biallelic rare missense variants in ADA2 with a minor allele frequency of less than 0.005. Of the 7 distinct variants present in these 4 patients, 6 had previously been reported as causative for DADA2, and the remaining variant is computationally predicted to be damaging to protein function. Four additional patients were carriers for monoallelic variants, one of which has been reported in DADA2 before. Serum samples from 2 patients with PAN with biallelic variants were available and showed markedly reduced ADA2 enzyme activity. ADA2 enzyme activity testing of 86 additional patients revealed 1 individual with strongly reduced ADA2 activity without detectable pathogenic variants. Patients with PAN and biallelic variants in ADA2 were younger at diagnosis than patients with 1 or no variant at ADA2, with no other clinical differences noted. Of 1107 patients with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA), none were homozygous or compound heterozygous for ADA2 mutations. A manuscript describing these findings was published in Arthritis and Rheumatology in March. 2) Description of LINKED, an X-linked recessive disorder presenting with multiple congenital anomalies and hemizygous mutations in OTUD5 Relying on genomic constraint scores, we identified 10 patients with multiple congenital anomalies caused by hemizygous variants in OTUD5, encoding a K48/K63 linkage-specific deubiquitylase. In collaboration with Achim Werner in NIDCR, we found that OTUD5 controls neuroectodermal differentiation through cleaving K48-linked ubiquitin chains to counteract degradation of select chromatin regulators (e.g., ARID1A/B, histone deacetylase 2, and HCF1), mutations of which underlie diseases that exhibit phenotypic overlap with OTUD5 patients. Loss of OTUD5 during differentiation leads to less accessible chromatin at neuroectodermal enhancers and aberrant gene expression. This study defined a previously unidentified disorder we named LINKED (LINKage-specific deubiquitylation deficiency-induced Embryonic Defects) syndrome that reveals linkage-specific ubiquitin cleavage from chromatin remodelers as an essential signaling mode that coordinates chromatin remodeling during embryogenesis. A paper describing these findings was published in Science Advances in January. 3) Autoinflammation due to TBK1 deficiency A collaborative study with Dusan Bogunovic identified four patients, ages 32, 26, 7, and 8 from 3 unrelated consanguineous families with homozygous loss-of-function mutations in TBK1, a regulator of IFN-I, NF-kB, and TNF-induced RIPK1-dependent cell death (RCD). All 4 patients suffer from chronic and systemic autoinflammation, but not severe viral infections. We found that TBK1 loss results in hypomorphic but sufficient IFN-I induction via RIG-I/MDA5, while the system retains near intact IL-6 induction through NF-kB. Autoinflammation is driven by TNF-induced RCD as patient-derived fibroblasts experienced higher rates of necroptosis in vitro, and CC3 was elevated in peripheral blood ex vivo. Treatment with anti-TNF dampened the baseline circulating inflammatory profile and ameliorated the clinical condition in vivo. These findings highlight the plasticity of the IFN-I response and underscore a cardinal role for TBK1 in the regulation of RCD. A manuscript describing these findings was published in Cell in August.