Cytoskeletal abnormalities and neutrophil dysfunction in WDR1 deficiency

Abstract

Cell motility, division, and structural integrity depend on dynamic remodeling of the cellular cytoskeleton, which is regulated in part by actin polymerization and depolymerization. In 3 families, we identified 4 children with recurrent infections and varying clinical manifestations including mild neutropenia, impaired wound healing, severe stomatitis with oral stenosis, and death. All patients studied had similar distinctive neutrophil herniation of the nuclear lobes and agranular regions within the cytosol. Chemotaxis and chemokinesis were markedly impaired, but staphylococcal killing was normal, and neutrophil oxidative burst was increased both basally and on stimulation. Neutrophil spreading on glass and cell polarization were also impaired. Neutrophil F-actin was elevated fourfold, suggesting an abnormality in F-actin regulation. Two-dimensional differential in-gel electrophoresis identified abnormal actin-interacting protein 1 (Aip1), encoded by WDR1, in patient samples. Biallelic mutations in WDR1 affecting distinct antiparallel β-strands of Aip1 were identified in all patients. It has been previously reported that Aip1 regulates cofilin-mediated actin depolymerization, which is required for normal neutrophil function. Heterozygous mutations in clinically normal relatives confirmed that WDR1 deficiency is autosomal recessive. Allogeneic stem cell transplantation corrected the immunologic defect in 1 patient. Mutations in WDR1 affect neutrophil morphology, motility, and function, causing a novel primary immunodeficiency.

Trp-Asp (WD) Repeat Domain 1 Is Essential for Mouse Peri-implantation Development and Regulates Cofilin Phosphorylation

“…Unexpectedly, we found that loss of WDR1 down-regulates P-Cofilin in all examined cells. Consistent with this, a very recent report showed that P-Cofilin is decreased in the cells of some patients with Wdr1 mutation (45). Interestingly, WDR1 seems to be present in an excessive amount in the cells, which well explains the discrepancies of Cofilin phosphorylation levels observed in knockdown and KO cells (36).…”

Primary immunodeficiencies caused by mutations in actin regulatory proteins

“…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 .…”

Studying human immunodeficiencies in humans: advances in fundamental concepts and therapeutic interventions

“…Examples of these discoveries are those caused by autosomal or hemizygous recessive mutations in BCL10 11 , CD70 12, 13 , CTPS1 14 , DOCK2 15 , MSN 16 , NIK 17 , RASGRP1 18 , RLTPR 19 , and TRFC 20 ; haploinsufficient mutations in IKAROS 21 or NFKB1 22 ; as well as a heterozygous dominant negative mutation in BCL11B 8 . Other examples include humoral immunodeficiency accompanying multi-organ autoimmunity caused by haploinsufficient mutations in CTLA4 23, 24 or gain-of-function mutations in STAT3 25 ; as well as neutrophil dysfunction caused by autosomal recessive mutations in JAGN1 26 or WDR1 27 . For the most part, these discoveries have dovetailed with findings previously made in mice but have revealed important aspects of the infectious context in which humans manifest disease.…”