Open AccessCharacterization of a L136P mutation in Formin-like 2 (FMNL2) from a patient with chronic inflammatory bowel disease
Author(s) -
Raphael Trefzer,
Orly Elpeleg,
T.V. Gabrusskaya,
Polina Stepensky,
Hagar MorShaked,
Robert Grosse,
Dominique Brandt
Publication year - 2021
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0252428
Subject(s) - formins , filopodia , actin , mutation , immune system , inflammatory bowel disease , biology , microbiology and biotechnology , podosome , immunology , cell , disease , medicine , actin cytoskeleton , genetics , pathology , cytoskeleton , gene
Diaphanous related formins are highly conserved proteins regulated by Rho-GTPases that act as actin nucleation and assembly factors. Here we report the functional characterization of a non-inherited heterozygous FMNL2 p.L136P mutation carried by a patient who presented with severe very early onset inflammatory bowel disease (IBD). We found that the FMNL2 L136P protein displayed subcellular mislocalization and deregulated protein autoinhibition indicating gain-of-function mechanism. Expression of FMNL2 L136P impaired cell spreading as well as filopodia formation. THP-1 macrophages expressing FMNL2 L136P revealed dysregulated podosome formation and a defect in matrix degradation. Our data indicate that the L136P mutation affects cellular actin dynamics in fibroblasts and immune cells such as macrophages.