L-plastin associated syndrome of immune deficiency and hematologic cytopenia
Raquel A Hernandez, James I. Hearn, Vijay Bhoopalan, Abdul Rezzak Hamzeh, Kristy Kwong, Koula E. M. Diamand, Ainsley R. Davies, Fei-Ju Li, Harish Padmanabhan, Rachel Milne, Fiona D. Ballard, Dominik Spensberger, Elizabeth E. Gardiner, Bahar Miraghazadeh, Anselm Enders, Matthew Cook
Abstract
Background LCP1 encodes L-plastin, an actin-bundling protein primarily expressed in hematopoietic cells. In mouse and fish models, LCP1 deficiency has been shown to result in hematologic and immune defects. Objective This study aimed to determine the nature of a human inborn error of immunity resulting from a novel genetic variant of LCP1 . Methods We performed genetic, protein, and cellular analysis of PBMCs from a kindred with apparent autosomal dominant immune deficiency. We identified a candidate causal mutation in LCP1 , which we evaluated by engineering the orthologous mutation in mice and Jurkat cells. Results A splice-site variant in LCP1 segregated with lymphopenia, neutropenia, and thrombocytopenia. The splicing defect resulted in at least 2 aberrant transcripts, producing an in-frame deletion of 24 nucleotides, and a frameshift deletion of exon 8. Cellular analysis of the kindred revealed a proportionate reduction of T and B cells and a mild expansion of transitional B cells. Similarly, mice carrying the orthologous genetic variant exhibited the same in-frame aberrant transcript, reduced expression Lcp1 and gene dose-dependent leukopenia, mild thrombocytopenia, and lymphopenia, with a significant reduction of T-cell populations. Functional analysis revealed that LCP1 c740 - 1G>A confers a defect in platelet development and function with aberrant spreading on collagen. Immunologic analysis revealed defective actin organization in T cells, reduced migration of PBMCs from patients, splenocytes from mutant mice, and a mutant Jurkat cell line in response to CXCL12; impaired germinal center B-cell expansion after immunization; and reduced cytokinesis during T cell proliferation. Conclusions We describe a unique human hematopoietic defect affecting neutrophils, lymphocytes, and platelets arising from partial LCP1 deficiency.