An ARHGAP25 variant links aberrant Rac1 function to early-onset skeletal fragility

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http://hdl.handle.net/10138/336620

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Mäkitie , R E , Henning , P , Jiu , Y , Kämpe , A , Kogan , K , Costantini , A , Välimäki , V-V , Medina-Gomez , C , Pekkinen , M , Salusky , I B , Schalin-Jäntti , C , Haanpää , M K , Rivadeneira , F , Bassett , J H D , Williams , G R , Lerner , U H , Pereira , R C , Lappalainen , P & Mäkitie , O 2021 , ' An ARHGAP25 variant links aberrant Rac1 function to early-onset skeletal fragility ' , JBMR plus , vol. 5 , no. 7 , 10509 . https://doi.org/10.1002/jbm4.10509

Title: An ARHGAP25 variant links aberrant Rac1 function to early-onset skeletal fragility
Author: Mäkitie, Riikka E.; Henning, Petra; Jiu, Yaming; Kämpe, Anders; Kogan, Konstantin; Costantini, Alice; Välimäki, Ville-Valtteri; Medina-Gomez, Carolina; Pekkinen, Minna; Salusky, Isidro B.; Schalin-Jäntti, Camilla; Haanpää, Maria K.; Rivadeneira, Fernando; Bassett, John H. Duncan; Williams, Graham R.; Lerner, Ulf H.; Pereira, Renata C.; Lappalainen, Pekka; Mäkitie, Outi
Other contributor: University of Helsinki, HUS Internal Medicine and Rehabilitation
University of Helsinki, Staff Services
University of Helsinki, Institute of Biotechnology
University of Helsinki, HUS Musculoskeletal and Plastic Surgery
University of Helsinki, CAMM - Research Program for Clinical and Molecular Metabolism
University of Helsinki, HUS Abdominal Center
University of Helsinki, Pekka Lappalainen / Principal Investigator
University of Helsinki, HUS Children and Adolescents















Date: 2021-07
Language: eng
Number of pages: 19
Belongs to series: JBMR plus
ISSN: 2473-4039
DOI: https://doi.org/10.1002/jbm4.10509
URI: http://hdl.handle.net/10138/336620
Abstract: Ras homologous guanosine triphosphatases (RhoGTPases) control several cellular functions, including cytoskeletal actin remodeling and cell migration. Their activities are downregulated by GTPase-activating proteins (GAPs). Although RhoGTPases are implicated in bone remodeling and osteoclast and osteoblast function, their significance in human bone health and disease remains elusive. Here, we report defective RhoGTPase regulation as a cause of severe, early-onset, autosomal-dominant skeletal fragility in a three-generation Finnish family. Affected individuals (n = 13) presented with multiple low-energy peripheral and vertebral fractures despite normal bone mineral density (BMD). Bone histomorphometry suggested reduced bone volume, low surface area covered by osteoblasts and osteoclasts, and low bone turnover. Exome sequencing identified a novel heterozygous missense variant c.652G>A (p.G218R) in ARHGAP25, encoding a GAP for Rho-family GTPase Rac1. Variants in the ARHGAP25 5 ' untranslated region (UTR) also associated with BMD and fracture risk in the general population, across multiple genomewide association study (GWAS) meta-analyses (lead variant rs10048745). ARHGAP25 messenger RNA (mRNA) was expressed in macrophage colony-stimulating factor (M-CSF)-stimulated human monocytes and mouse osteoblasts, indicating a possible role for ARHGAP25 in osteoclast and osteoblast differentiation and activity. Studies on subject-derived osteoclasts from peripheral blood mononuclear cells did not reveal robust defects in mature osteoclast formation or resorptive activity. However, analysis of osteosarcoma cells overexpressing the ARHGAP25 G218R-mutant, combined with structural modeling, confirmed that the mutant protein had decreased GAP-activity against Rac1, resulting in elevated Rac1 activity, increased cell spreading, and membrane ruffling. Our findings indicate that mutated ARHGAP25 causes aberrant Rac1 function and consequently abnormal bone metabolism, highlighting the importance of RhoGAP signaling in bone metabolism in familial forms of skeletal fragility and in the general population, and expanding our understanding of the molecular pathways underlying skeletal fragility. (c) 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
Subject: OSTEOGENESIS IMPERFECTA
OSTEOPOROSIS
BONE MODELING AND REMODELING
CELL
TISSUE SIGNALING
OTHER
GENETIC RESEARCH
GTPASE-ACTIVATING PROTEINS
GENOME-WIDE ASSOCIATION
BONE-MINERAL DENSITY
RHO-GTPASES
BETA-CATENIN
MUTATIONS
IDENTIFICATION
METAANALYSIS
OSTEOCLASTS
3121 General medicine, internal medicine and other clinical medicine
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