TY - JOUR
T1 - Germ line LCP1 mutations cause immunodeficiency with neutropenia, monocytopenia, lymphopenia, and defective cytokinesis
AU - van Bergen, Thijs
AU - Bosch, Dennis A.
AU - Bellanné-Chantelot, Christine
AU - Mulet-Lazaro, Roger
AU - Bledsoe, Jacob R.
AU - Chen, Lanpeng
AU - de Looper, Hans W.J.
AU - van Dijk, Claire
AU - ter Borg, Mariette N.D.
AU - Bindels, Eric M.J.
AU - Hoogenboezem, Remco M.
AU - Roovers, Onno
AU - Olofsen, Patricia A.
AU - Bartels, Marije
AU - van Montfrans, Joris
AU - Breed, Puck
AU - Salzer, Elisabeth
AU - Holierhoek, Marloes G.
AU - Nelken, Brigitte
AU - Beaupain, Blandine
AU - Fleming, Mark D.
AU - Shimamura, Akiko
AU - Raaijmakers, Marc H.G.P.
AU - Donadieu, Jean
AU - Newburger, Peter E.
AU - Touw, Ivo P.
AU - Aalbers, Anna M.
N1 - Publisher Copyright:
© 2026 The American Society of Hematology
PY - 2026/2/10
Y1 - 2026/2/10
N2 - Severe congenital neutropenia (SCN) is characterized by neutropenia, recurrent infections, and an increased leukemia risk. Multiple genetic defects that underlie SCN have been identified, but a genetic diagnosis is still lacking in a significant proportion of patients. In this study, we report 4 independent pedigrees with heterozygous variants in LCP1. Variants c.740-1G>T and c.740-20_744del produced the same alternatively spliced RNA product, causing an in-frame deletion (p.A247_E254del). Variant c.509C>T in the third pedigree produced p.S170L, and variant c.806T>C in the fourth pedigree produced p.L269P. Affected individuals suffered from neutropenia, poor or complete lack of response to granulocyte colony–stimulating factor (G-CSF) treatment, and variable degrees of lymphopenia, hypogammaglobulinemia, and monocytopenia. Patients with A247_E254del and p.L269P presented with tetraploid cells in the bone marrow, indicative of disturbed cytokinesis. In one of these kindreds, 2 individuals developed acute leukemia. G-CSF nonresponsiveness and defective cell cycling were repaired upon correction of the LCP1 A247_E254del variant in patient-derived induced pluripotent stem cells, supporting the monogenic origin of the disease. Indicative of their gain-of-function effect, both the A247_E254del and S170L variants increased F-actin bundling and the formation of abnormal protrusions. Single-cell transcriptome analysis of A247_E254del bone marrow-derived hematopoietic stem and progenitor cells (HSPCs) showed deregulation of signaling pathways that control mitosis in multilineage and lymphoid-primed HSPC subsets. We concluded that activating LCP1 variants cause a new hematopoietic disorder with autosomal dominant inheritance. Depending on the consequences of the LCP1 variants in terms of protein structure, patients may suffer from G-CSF refractory severe neutropenia, lymphopenia, hypogammaglobulinemia, monocytopenia, and defective cytokinesis.
AB - Severe congenital neutropenia (SCN) is characterized by neutropenia, recurrent infections, and an increased leukemia risk. Multiple genetic defects that underlie SCN have been identified, but a genetic diagnosis is still lacking in a significant proportion of patients. In this study, we report 4 independent pedigrees with heterozygous variants in LCP1. Variants c.740-1G>T and c.740-20_744del produced the same alternatively spliced RNA product, causing an in-frame deletion (p.A247_E254del). Variant c.509C>T in the third pedigree produced p.S170L, and variant c.806T>C in the fourth pedigree produced p.L269P. Affected individuals suffered from neutropenia, poor or complete lack of response to granulocyte colony–stimulating factor (G-CSF) treatment, and variable degrees of lymphopenia, hypogammaglobulinemia, and monocytopenia. Patients with A247_E254del and p.L269P presented with tetraploid cells in the bone marrow, indicative of disturbed cytokinesis. In one of these kindreds, 2 individuals developed acute leukemia. G-CSF nonresponsiveness and defective cell cycling were repaired upon correction of the LCP1 A247_E254del variant in patient-derived induced pluripotent stem cells, supporting the monogenic origin of the disease. Indicative of their gain-of-function effect, both the A247_E254del and S170L variants increased F-actin bundling and the formation of abnormal protrusions. Single-cell transcriptome analysis of A247_E254del bone marrow-derived hematopoietic stem and progenitor cells (HSPCs) showed deregulation of signaling pathways that control mitosis in multilineage and lymphoid-primed HSPC subsets. We concluded that activating LCP1 variants cause a new hematopoietic disorder with autosomal dominant inheritance. Depending on the consequences of the LCP1 variants in terms of protein structure, patients may suffer from G-CSF refractory severe neutropenia, lymphopenia, hypogammaglobulinemia, monocytopenia, and defective cytokinesis.
UR - https://www.scopus.com/pages/publications/105028488800
U2 - 10.1182/bloodadvances.2025016507
DO - 10.1182/bloodadvances.2025016507
M3 - Article
C2 - 41056520
AN - SCOPUS:105028488800
SN - 2473-9529
VL - 10
SP - 627
EP - 641
JO - Blood Advances
JF - Blood Advances
IS - 3
ER -