Nckap1l Defects Lead to a Novel Syndrome Combining Immunodeficiency, Lymphoproliferation, and Hyperinflammation Publisher Pubmed



Castro CN¹ ; Rosenzwajg M^{1, 2} ; Carapito R^{5, 6} ; Shahrooei M^{7, 8} ; Konantz M⁹ ; Khan A^{10, 11, 12} ; Miao Z^{13, 14} ; Gro M¹ ; Tranchant T⁵ ; Radosavljevic M^{5, 6} ; Paul N⁵ ; Stemmelen T⁵ ; Pitoiset F² ; Hirschler A¹⁵ Show All Authors
Source: Journal of Experimental Medicine Published:2020

Abstract

The Nck-associated protein 1-like (NCKAP1L) gene, alternatively called hematopoietic protein 1 (HEM-1), encodes a hematopoietic lineage-specific regulator of the actin cytoskeleton. Nckap1l-deficient mice have anomalies in lymphocyte development, phagocytosis, and neutrophil migration. Here we report, for the first time, NCKAP1L deficiency cases in humans. In two unrelated patients of Middle Eastern origin, recessive mutations in NCKAP1L abolishing protein expression led to immunodeficiency, lymphoproliferation, and hyperinflammation with features of hemophagocytic lymphohistiocytosis. Immunophenotyping showed an inverted CD4/CD8 ratio with a major shift of both CD4+ and CD8+ cells toward memory compartments, in line with combined RNA-seq/proteomics analyses revealing a T cell exhaustion signature. Consistent with the core function of NCKAP1L in the reorganization of the actin cytoskeleton, patients' T cells displayed impaired early activation, immune synapse morphology, and leading edge formation. Moreover, knockdown of nckap1l in zebrafish led to defects in neutrophil migration. Hence, NCKAP1L mutations lead to broad immune dysregulation in humans, which could be classified within actinopathies. © 2020 Rockefeller University Press. All rights reserved.