Characterization of a L136P mutation in Formin-like 2 (FMNL2) from a patient with chronic inflammatory bowel disease.

Raphael Trefzer,Hagar Mor-Shaked,Tatyana Gabrusskaya,Polina Stepensky,Robert Grosse,Orly Elpeleg,Dominique T Brandt,Yulia Komarova

doi:10.1371/journal.pone.0252428

Raphael Trefzer, Hagar Mor-Shaked + Show 6 more

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https://doi.org/10.1371/journal.pone.0252428

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Abstract

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.

Highlights

Over the last decade many research efforts were devoted towards identifying genetic components of intestinal inflammation
Formin mutations can result in various forms of pathologies like the Charcot-Marie-Tooth-Syndrome and Focal Segmental Glomerulosclerosis (FSGS) which are associated with mutations of INF2 [18,19]
A heterozygous FMNL2 p.Leu136Pro mutation was identified by whole exome sequencing (WES) of a peripheral blood sample and was found to occur de novo, i.e. was not inherited from the parents

Summary

Introduction

Over the last decade many research efforts were devoted towards identifying genetic components of intestinal inflammation. Genome-wide association studies (GWAS) addressed the identification of IBD-related genes and found over 200 gene loci that were associated with developing Crohn’s disease (CD) or Ulcerative colitis (UC) [1,2,3,4,5] These findings pictured the wide field of genetic influence on IBD that has to be further evaluated regarding the relevance in individual cases. Formin mutations can result in various forms of pathologies like the Charcot-Marie-Tooth-Syndrome and Focal Segmental Glomerulosclerosis (FSGS) which are associated with mutations of INF2 [18,19] Despite their relevance in various actindependent cell functions, a role of formins in the pathomechanisms of IBD and immune defects has not yet been described. We report the first characterization of a formin mutation that is associated with inflammatory bowel disease (IBD)

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