ECTS2014 Oral Communications Genetics of bone disease (6 abstracts)
PLS3 mutations in X-linked osteoporosis with fractures
M Carola Zillikens 2 , Fleur S van Dijk 1 , Dimitra Micha 1 , Markus Riessland 3 , Carlo LM Marcelis 4 , Christine E de-Die Smulders 5 , Janine Milbradt 3 , Anton A Franken 6 , Arjan J Harsevoort 7 , Klaske D Lichtenbelt 8 , J van de Peppel 2 , Hans E Pruijs 9 , M Estela Rubio-Gozalbo 10, , Rolf Zwertbroek 12 , Youssef Moutaouakil 1 , Jaqueline Egthuijsen 1 , B van der Eerden 2 , Matthias Hammerschmidt 13 , Renate Bijman 1 , Cor M Semeins 14 , Astrid D Bakker 14 , Vincent Everts 14 , Jenneke Klein-Nulend 14 , Natalia Campos-Obando 2 , Albert Hofman 15 , Gerard J te Meerman 16 , JP van Leeuwen 2 , Annemieke JMH Verkerk 2 , André G Uitterlinden 2, , Alessandra Maugeri 1 , Erik A Sistermans 1 , Quinten Waisfisz 1 , Hanne Meijers-Heijboer 1 , Brunhilde Wirth 3 , Marleen EH Simon 17 & Gerard Pals 1
1Center for Connective Tissue Disorders, Department of Clinical Genetics, VU University Medical Center, Amsterdam, the Netherlands; 2Department of Internal Medicine, Erasmus MC, Rotterdam, the Netherlands; 3Institute of Human Genetics, Institute for Genetics and Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany; 4Department of Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands; 5Department of Clinical Genetics, Maastricht University Medical Centre, Maastricht, the Netherlands; 6Department of Internal Medicine, Isala Clinics Zwolle, Zwolle, the Netherlands; 7Department of Orthopedics, Isala Clinics Zwolle, Zwolle, the Netherlands; 8Department of Medical Genetics, University Medical Center Utrecht, Utrecht, the Netherlands; 9Department of Pediatric Orthopaedics, University Medical Center Utrecht, Wilhelmina Childrens Hospital, Utrecht, the Netherlands; 10Department of Pediatrics, Maastricht University Medical Center, Maastricht, the Netherlands; 11Department of Pediatrics and Laboratory Genetic Metabolic Diseases, Maastricht University Medical Center, Maastricht, the Netherlands; 12Department of Internal Medicine, Westfries Gasthuis, Hoorn, the Netherlands; 13Department of Developmental Biology, University of Cologne, Cologne, Germany; 14Department of Oral Cell Biology, ACTA, University of Amsterdam and VU University Amsterdam, MOVE Research Institute Amsterdam, Amsterdam, the Netherlands; 15Department of Epidemiology, Erasmus MC, Rotterdam, the Netherlands; 16Department of Genetics, University Medical Center Groningen, University of Groningen, the Netherlands; 17Department of Clinical Genetics, Erasmus MC, Rotterdam, the Netherlands.
Background: We identified a family with early onset X-linked osteoporosis and fractures
Methods: We performed whole exome sequencing of the X chromosome in three affected members. After discovering a putative pathogenic variant we performed Sanger sequencing of all exons of this gene in other members of this family and in 95 unrelated men suspected of OI type I without COL1A1/2 mutations. We also genotyped a SNP in this gene (minor allele frequency 0.02) in elderly subjects in three cohorts of a prospective population-based study for association analyses with BMD and incident fractures. We performed functional studies in zebrafish after pls3 knock-down and expression analysis of PLS3 in human differentiating mesenchymal stem cells (MSCs) and in differentiating human osteoclasts.
Results: We discovered five pathogenic variants in PLS3 in five families with osteoporosis and osteoporotic fractures. Furthermore, a rare SNP in PLS3 (rs140121121) was associated with a twofold increased fracture risk in heterozygous postmenopausal women in a population-based study and with decreased BMD, although increased fracture risk was not fully explained by BMD. PLS3 is expressed during osteogenic and decreased during adipogenic differentiation of MSCs and its expression increased during differentiation and activation of osteoclasts. Knock-down experiments in zebrafish showed malformations of the developing craniofacial bone structure, body axis and tail that could be rescued dose-dependently by human PLS3 mRNA, supporting the concept that PLS3 is a bone regulatory protein.
Conclusion: We identified loss-of-function variants in PLS3 as a monogenetic cause of X-linked osteoporosis and osteoporotic fractures and found a rare SNP in this gene associated with a twofold increased fracture risk and decreased BMD in heterozygous women in a population-based study, indicating genetic variation in PLS3 as a novel factor involved in common, multifactorial osteoporosis.
Article tools
My recent searches
My recently viewed abstracts
Authors
Bone Abstracts
ISSN 2052-1219 (online)
© Bioscientifica 2024 |
Privacy policy |
Cookie settings
BiosciAbstracts
Bioscientifica Abstracts is the gateway to a series of products that provide a permanent, citable record of abstracts for biomedical and life science conferences.
Find out more