Autosomal dominant gain-of-function mutations in LCP1 cause a syndromic neutropenia and immunodeficiency.

Authors

Lang Yu, Bo Zhou, Wei Liu, Wenhui Li, Qinglv Wei, Yishi Zhang, Chen Li, Wendao Li, Yulin Li, Guangzhao Li, Gan Sun, Rui Gan, Ran Chen, Wenjing Zhang, Anle Zeng, Rongtao Zhao, Wenli He, Yanjun Jia, Lina Zhou, Zhiyong Zhang, Xuemei Tang, Xiang Qiu, Qing Zhou, Wenxia Song, Xiaodong Zhao, Yunfei An

Published in

Genes & diseases. Volume 14. Issue 1. Pages 102232. Epub May 12, 2026.

Abstract

Actin cytoskeleton defects underlie immuno-actinopathies. We identified three patients with heterozygous LCP1 gain-of-function mutations (L362F, A365D) causing activated LCP1-associated immunodeficiency syndrome, characterized by congenital neutropenia, variable combined immunodeficiency, and allergy. Patients' neutrophils show maturation arrest and excessive apoptosis, while T/B cells are reduced and functionally impaired. Patient-derived iPSCs, CRISPR-edited cells, and LCP1^+/L362F mice replicate these defects. Mechanistically, mutant LCP1 hyper-bundles F-actin, inducing VDAC1 oligomerization and mitochondrial apoptosis. This study further establishes LCP1 as a regulator of immune cell fate and suggests targeting actin dynamics as therapy.

PMID:
42763497
Bibliographic data and abstract were imported from PubMed on 20 Sep 2026.

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