Family-based whole-exome sequencing implicates a variant in lysyl oxidase like 4 in atypical femur fractures.

Autor:	Zhou W; Department of Internal Medicine, Erasmus MC, Erasmus University Medical Center, Rotterdam, the Netherlands., van de Laarschot DM; Department of Internal Medicine, Erasmus MC, Erasmus University Medical Center, Rotterdam, the Netherlands., van Rooij JGJ; Department of Internal Medicine, Erasmus MC, Erasmus University Medical Center, Rotterdam, the Netherlands., Koedam M; Department of Internal Medicine, Erasmus MC, Erasmus University Medical Center, Rotterdam, the Netherlands., Nguyen HH; Department of Medicine, School of Clinical Sciences, Monash University, Clayton, Australia., Uitterlinden AG; Department of Internal Medicine, Erasmus MC, Erasmus University Medical Center, Rotterdam, the Netherlands., Ebeling PR; Department of Medicine, School of Clinical Sciences, Monash University, Clayton, Australia., Thakker RV; Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom.; National Institute for Health Research Oxford Biomedical Research Centre, Oxford, United Kingdom., Geusens P; Biomedical Research Institute, University Hasselt, Diepenbeek, Belgium.; Department of Internal Medicine, Maastricht University, Maastricht, Netherlands., van der Eerden BCJ; Department of Internal Medicine, Erasmus MC, Erasmus University Medical Center, Rotterdam, the Netherlands., Verkerk AJMH; Department of Internal Medicine, Erasmus MC, Erasmus University Medical Center, Rotterdam, the Netherlands., Zillikens MC; Department of Internal Medicine, Erasmus MC, Erasmus University Medical Center, Rotterdam, the Netherlands.
Jazyk:	angličtina
Zdroj:	Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research [J Bone Miner Res] 2024 Nov 01. Date of Electronic Publication: 2024 Nov 01.
DOI:	10.1093/jbmr/zjae175
Abstrakt:	Atypical femur fractures (AFFs) are rare adverse events associated with bisphosphonate use, having unclear pathophysiology. AFFs also cluster in families and have occurred in patients with monogenetic bone diseases sometimes without bisphosphonate use, suggesting an underlying genetic susceptibility. Our aim was to identify a genetic cause for AFF in a Caucasian family with seven members affected by osteoporosis, including three siblings with bisphosphonate-associated AFFs. Using whole-exome sequencing, we identified a rare pathogenic variant c.G1063A (p.Gly355Ser) in lysyl oxidase like 4 (LOXL4) among 64 heterozygous rare, protein-altering variants shared by the three siblings with AFFs. The same variant was also found in a fourth sibling with a low-trauma femur fracture above the knee, not fulfilling all the ASBMR criteria of AFF and in one of 73 unrelated European AFF patients. LOXL4 is involved in collagen cross-linking and may be relevant for microcrack formation and bone repair mechanisms. Preliminary functional analysis showed that skin fibroblast-derived osteoblasts from the unrelated patient with the LOXL4 variant expressed less collagen type I and elastin, while osteogenic differentiation and mineralization were enhanced compared with two controls. In conclusion, this LOXL4 variant may underlie AFF susceptibility possibly due to abnormal collagen metabolism leading to increased formation of microdamage or compromised healing of microcracks in the femur. (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research.)
Databáze:	MEDLINE
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