Autosomal dominant gain-of-function mutations in LCP1 cause a syndromic neutropenia and immunodeficiency
Lang Yu1,2, Bo Zhou3, Wei Liu4
1National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing 400014, China.
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.
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