Bone Abstracts (2014) 3 OC4.1 | DOI: 10.1530/boneabs.3.OC4.1

PLS3 mutations in X-linked osteoporosis with fractures

M Carola Zillikens2, Fleur S van Dijk1, Dimitra Micha1, Markus Riessland3, Carlo LM Marcelis4, Christine E de-Die Smulders5, Janine Milbradt3, Anton A Franken6, Arjan J Harsevoort7, Klaske D Lichtenbelt8, J van de Peppel2, Hans E Pruijs9, M Estela Rubio-Gozalbo10,11, Rolf Zwertbroek12, Youssef Moutaouakil1, Jaqueline Egthuijsen1, B van der Eerden2, Matthias Hammerschmidt13, Renate Bijman1, Cor M Semeins14, Astrid D Bakker14, Vincent Everts14, Jenneke Klein-Nulend14, Natalia Campos-Obando2, Albert Hofman15, Gerard J te Meerman16, JP van Leeuwen2, Annemieke JMH Verkerk2, André G Uitterlinden2,15, Alessandra Maugeri1, Erik A Sistermans1, Quinten Waisfisz1, Hanne Meijers-Heijboer1, Brunhilde Wirth3, Marleen EH Simon17 & Gerard Pals1


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.

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