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L-plastin associated syndrome of immune deficiency and haematological cytopenia (PASIC).

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 hematological and immune defects.

OBJECTIVE: 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 results in at least two aberrant transcripts, producing an in-frame deletion of 24 nucleotides, and a frameshifting 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 LCP1c740-1G>A confers a defect in platelet development and function with aberrant spreading on collagen. Immunological analysis revealed defective actin organisation 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 centre B cell expansion after immunisation, and reduced cytokinesis during T cell proliferation.

CONCLUSION: We describe a unique human hematopoietic defect affecting neutrophils, lymphocytes and platelets, arising from partial LCP1 deficiency.

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