Autoinflammatory periodic fever, immunodeficiency, and thrombocytopenia (PFIT) caused by mutation in actin-regulatory gene WDR1

Abstract

Standing et al. report a novel autoinflammatory disease caused by a homozygous missense mutation in the actin-regulating protein WDR1. The disease is characterized by periodic fevers, immunodeficiency, and thrombocytopenia, with increased polymerized actin in immune cells and increased IL-18 secretion.

Primary immunodeficiencies caused by mutations in actin regulatory proteins

“…Transfected cells form aggregates of mutated WDR1 protein that co-localizes with pyrin. 205 This is similar to the elevated levels of IL-18 observed in mice expressing a hypomorphic allele of WDR1. These mice also have a spontaneous autoinflammatory disease and thrombocytopenia.…”

“…Two siblings with a homozygous WDR1 missense mutation predicted to disrupt intramolecular interactions were identified with periodic fevers and high serum levels of the pro‐inflammatory cytokine IL‐18. Transfected cells form aggregates of mutated WDR1 protein that co‐localizes with pyrin . This is similar to the elevated levels of IL‐18 observed in mice expressing a hypomorphic allele of WDR1.…”

“…Three reports have been published identifying children with autosomal recessive missense mutations in the WDR1 gene. WDR1 deficient patients have frequent infections, severe stomatitis, and impaired wound healing . Their neutrophils have elevated basal F‐actin levels with impaired spreading, polarization, adhesion, and chemotaxis .…”

“…WDR1 deficient patients have frequent infections, severe stomatitis, and impaired wound healing. [203][204][205] Their neutrophils have elevated basal F-actin levels with impaired spreading, polarization, adhesion, and chemotaxis. 203,204 WDR1 deficient neutrophils also have augmentation of their oxidative burst.…”

Monogenic autoinflammatory disorders: beyond the periodic fever

“…AGS, Aicardi-Goutières syndrome, AIADK, autoinflammation with arthritis and dyskeratosis; AIFEC, autoinflammation with infantile enterocolitis; AILJK, autoimmune interstitial lung, joint, and kidney disease; APLAID, autoinflammation, antibody deficiency, and immune dysregulation syndrome; DADA2, deficiency of ADA2; DIRA, interleukin 1 receptor antagonist deficiency; DITRA, interleukin 36 receptor antagonist deficiency; EOIBD, early onset inflammatory bowel disease; FMF, familial Mediterranean fever; H+ syndrome, histiocytosis-lymphadenopathy plus syndrome;HA20, haploinsufficiency of A20; HS, hidradenitis suppurativa; HYDM1, hydatidiform mole, recurrent 1; JIA, juvenile idiopathic arthritis; MKD, mevalonate kinase deficiency; MSPC, multiple self-healing palmoplantar carcinoma; ORAS, otulinrelated autoinflammatory syndrome; PAAND, pyrin associated autoinflammation with neutrophilic dermatosis; PAPA, syndrome pyogenic sterile arthritis, pyoderma gangrenosum, and acne syndrome; PFIT, autoinflammatory periodic fever, immunodeficiency, and thrombocytopenia; PLAID, PLCG2 associated antibody deficiency and immune dysregulation; PRAAS, proteasome-associated autoinflammatory syndrome; PRP, pityriasis rubra pilaris, SAVI, STING-associated vasculopathy, infantile-onset; SIFD, sideroblastic anaemia with B-cell immunodeficiency, periodic fevers, and developmental delay; SPENCDI, spondyloenchondrodysplasia with immune dysregulation; TRAPS, tumour necrosis factor receptor-associated periodic syndrome; XLPDR, X-linked pigmentary disorder, reticulate, with systemic manifestations. [136][137][138][139]…”