PLS3 Deletions Lead to Severe Spinal Osteoporosis and Disturbed Bone Matrix Mineralization

Anders J. Kämpe*, Alice Costantini, Yael Levy-shraga, Leonid Zeitlin, Paul Roschger, Fulya Taylan, Anna Lindstrand, Eleftherios P. Paschalis, Sonja Gamsjaeger, Annick Raas-Rothschild, Matthias Hövel, Hong Jiao, Klaus Klaushofer, Corinna Grasemann, Outi Mäkitie

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Mutations in the PLS3 gene, encoding Plastin 3, were described in 2013 as a cause for X-linked primary bone fragility in children. The specific role of PLS3 in bone metabolism remains inadequately understood. Here we describe for the first time PLS3 deletions as the underlying cause for childhood-onset primary osteoporosis in 3 boys from 2 families. We carried out thorough clinical, radiological, and bone tissue analyses to explore the consequences of these deletions and to further elucidate the role of PLS3 in bone homeostasis. In family 1, the 2 affected brothers had a deletion of exons 4–16 (NM_005032) in PLS3, inherited from their healthy mother. In family 2, the index patient had a deletion involving the entire PLS3 gene (exons 1–16), inherited from his mother who had osteoporosis. The 3 patients presented in early childhood with severe spinal compression fractures involving all vertebral bodies. The 2 brothers in family 1 also displayed subtle dysmorphic facial features and both had developed a myopathic gait. Extensive analyses of a transiliac bone biopsy from 1 patient showed a prominent increase in osteoid volume, osteoid thickness, and in mineralizing lag time. Results from quantitative backscattered electron imaging and Raman microspectroscopy showed a significant hypomineralization of the bone. Together our results indicate that PLS3 deletions lead to severe childhood-onset osteoporosis resulting from defective bone matrix mineralization, suggesting a specific role for PLS3 in the mineralization process.

Original languageEnglish
Pages (from-to)2394-2404
Number of pages11
JournalJournal of Bone and Mineral Research
Volume32
Issue number12
DOIs
StatePublished - Dec 2017

Funding

FundersFunder number
Folkh€alsan Research Foundation
Ludwig Boltzmann Institute of Osteology
Helsingin ja Uudenmaan Sairaanhoitopiiri
Folkhälsanin Tutkimussäätiö
Academy of Finland
Karolinska Institutet
Stockholms Läns Landsting
Vetenskapsrådet
Sigrid Juséliuksen Säätiö
Barncancerfonden
Allgemeine Unfallversicherungsanstalt
Novo Nordisk Fonden
Uppsala Multidisciplinary Center for Advanced Computational Science

    Keywords

    • BONE HISTOMORPHOMETRY
    • DXA
    • GENETIC RESEARCH
    • MATRIX MINERALIZATION
    • OSTEOPOROSIS

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