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PLS3 Mutations in X-Linked Osteoporosis with Fractures

2013; Massachusetts Medical Society; Volume: 369; Issue: 16 Linguagem: Inglês

10.1056/nejmoa1308223

1533-4406

Fleur S. van Dijk, M. Carola Zillikens, Dimitra Micha, Markus Rießland, Carlo Marcelis, C E de Die-Smulders, Janine Milbradt, Anton Franken, Arjan J. Harsevoort, Klaske D. Lichtenbelt, Hans E. Pruijs, M. Estela Rubio‐Gozalbo, Rolf Zwertbroek, Youssef Moutaouakil, Jaqueline Egthuijsen, Matthias Hammerschmidt, Renate Bijman, C.M. Semeins, Astrid D. Bakker, Vincent Everts, Jenneke Klein‐Nulend, Natalia Campos‐Obando, Albert Hofman, Gerard J. te Meerman, Annemieke J.M.H. Verkerk, André G. Uitterlinden, Alessandra Maugeri, Erik A. Sistermans, Quinten Waisfisz, Hanne Meijers‐Heijboer, Brunhilde Wirth, Marleen Simon, Gerard Pals,

Bone and Dental Protein Studies

Plastin 3 (PLS3), a protein involved in the formation of filamentous actin (F-actin) bundles, appears to be important in human bone health, on the basis of pathogenic variants in PLS3 in five families with X-linked osteoporosis and osteoporotic fractures that we report here. The bone-regulatory properties of PLS3 were supported by in vivo analyses in zebrafish. Furthermore, in an additional five families (described in less detail) referred for diagnosis or ruling out of osteogenesis imperfecta type I, a rare variant (rs140121121) in PLS3 was found. This variant was also associated with a risk of fracture among elderly heterozygous women that was two times as high as that among noncarriers, which indicates that genetic variation in PLS3 is a novel etiologic factor involved in common, multi-factorial osteoporosis.