L-plastin associated syndrome of immune deficiency and hematologic cytopenia - 04/06/24

Doi : 10.1016/j.jaci.2024.05.001

Raquel A. Hernandez, MSc ^a, James I. Hearn, PhD ^b, Vijay Bhoopalan, MSc ^b, Abdul Rezzak Hamzeh, PhD ^c, Kristy Kwong, PhD ^d,^e, Koula Diamand, PhD ^d, Ainsley Davies, PhD ^d, Fei-Ju Li, PhD ^d, Harish Padmanabhan, PhD ^d, Rachel Milne, BCom ^d, Fiona Ballard, BSc ^a, Dominik Spensberger, PhD ^d, Elizabeth E. Gardiner, PhD ^b, Bahar Miraghazadeh, PhD ^a,^{^{∗
These authors contributed equally to this work.}}, Anselm Enders, MD, PhD ^a,^{^{∗
These authors contributed equally to this work.}}, Matthew C. Cook, MBBS, PhD ^a,^c,^e,^⁎^{^{∗
These authors contributed equally to this work.}}
^a Division of Immunology and Infectious Diseases, John Curtin School of Medical Research, Australian National University, Canberra, Australia
^b Division of Genome Sciences and Cancer, John Curtin School of Medical Research, Australian National University, Canberra, Australia
^c Canberra Clinical Genomics, Canberra, Australia
^d Australian Phenomics Facility and John Curtin School of Medical Research, Australian National University, Canberra, Australia
^e Cambridge Institute of Therapeutic Immunology and Infectious Disease, Department of Medicine, University of Cambridge, Cambridge, United Kingdom

^∗Corresponding author: Matthew Cook, MBBS, PhD, Cambridge Institute for Therapeutic Immunology and Infectious Diseases, Department of Medicine, University of Cambridge, Puddicombe Way, Cambridge, CB2 0AW, UK.Cambridge Institute for Therapeutic Immunology and Infectious DiseasesDepartment of MedicineUniversity of CambridgePuddicombe WayCambridgeCB2 0AWUK

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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.