Lymphocyte cytosolic protein 1 (L-plastin) I232F mutation impairs granulocytic proliferation and causes neutropenia

Abstract

Neutrophils migrate into inflamed tissue, engage in phagocytosis, and clear pathogens or apoptotic cells. These processes require well-coordinated events involving the actin cytoskeleton. We describe a child with severe neutropenia and episodes of soft tissue infections and pneumonia. Bone marrow examination showed granulocytic hypoplasia with dysplasia. Whole exome sequencing revealed a de novo heterozygous missense mutation in LCP1, which encodes the F-actin binding protein Lymphocyte Cytosolic Protein 1. To determine its pathophysiologic significance, we stably transduced cells with a doxycycline-inducible wild type LCP1 and LCP1 I232F lentiviral constructs. We observed dysplastic granulocytic 32D cells expressing LCP1 I232F cells. These cells showed decreased proliferation without a block in differentiation. Additionally, expression of LCP1 I232F resulted in a cell cycle arrest at G2/M phase, but it did not lead to increased levels of genes involved in apoptosis or the unfolded protein response. Both 32D and HeLa cells expressing mutant LCP1 showed impaired cell motility and invasiveness. Flow cytometry showed increased F-actin. However, mutant LCP1-expressing 32D cells demonstrated normal oxidative burst upon stimulation. Confocal imaging and subcellular fractionation revealed diffuse intracellular localization of LCP1, but only the mutant form was found in the nucleus. We conclude that LCP1 is a new gene involved in granulopoiesis, and the missense variant LCP1 I232F leads to neutropenia and granulocytic dysplasia with aberrant actin dynamics. Our work supports a model of neutropenia due to aberrant actin regulation.

Inhibition of the Glycolysis Prevents the Cerebral Infarction Progression Through Decreasing the Lactylation Levels of LCP1

“…Ning et al found that LCP1 was upregulated and acted as a specific molecular marker of cancer recurrence and therapeutic targets in colon cancer [ 25 ]. Similarly, LCP1 was confirmed to promote the cell invasion and metastasis in prostate cancer cells, and the silencing experiment indicated that LCP1 might be an effective approach for tumors treatment [ 5 , 22 ]. On the other hand, Wen et al [ 11 ] performed a global proteomic analysis to explore the differently expressed genes in the cerebral ischemia–reperfusion injury through MCAO rat model.…”

“…As an actin-binding protein, Lymphocyte cytosolic protein 1 (LCP1) regulates cell movement mainly by interacting with actin, and is one of the main cytoskeleton binding proteins that directly control cell movement [ 5 ]. In addition, LCP1 is also involved in host defense, the formation of immune synapses, T cell activation, etc.…”

A machine learning model derived from analysis of time-course gene-expression datasets reveal temporally stable gene markers predictive of sepsis mortality

“…CX3CR1 , which serves as receptors for fractalkine, is important for the adhesion and migration of leukocytes (32), and considered to be a potential therapeutic target among septic patients (33). LCP1 encodes for lymphocyte cytosolic protein 1 and is involved in granulopoiesis (34) as well as activation of T cells (35). SHCBP1 encodes for SH2 domain binding protein 1 and is implicated in CD8+ T cell function (36).…”