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

IF 5.1 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM
Wei Zhou, Denise M van de Laarschot, Jeroen G J van Rooij, Marijke Koedam, Hanh H Nguyen, André G Uitterlinden, Peter R Ebeling, Rajesh V Thakker, Piet Geusens, Bram C J van der Eerden, Annemieke J M H Verkerk, M Carola Zillikens
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Abstract

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.

基于家族的全外显子组测序发现,非典型股骨骨折与类似赖氨酰氧化酶 4 的一个变体有关。
非典型股骨骨折(AFFs)是与使用双膦酸盐相关的罕见不良事件,其病理生理学尚不清楚。非典型股骨骨折也会出现在家族中,有时也会发生在未使用双膦酸盐的单基因骨病患者身上,这表明存在潜在的遗传易感性。我们的目的是在一个有七名骨质疏松症患者的白种人家族中找出 AFF 的遗传原因,其中包括三名患有与双磷酸盐相关的 AFF 的兄弟姐妹。通过全外显子组测序,我们在患有 AFFs 的三个兄弟姐妹共有的 64 个杂合罕见蛋白质改变变体中,发现了赖氨酰氧化酶样 4(LOXL4)中的一个罕见致病变体 c.G1063A(p.Gly355Ser)。在第四个患有膝上低创伤性股骨骨折的兄弟姐妹中也发现了同样的变异,但不符合ASBMR的所有AFF标准,在73个无血缘关系的欧洲AFF患者中也发现了一个同样的变异。LOXL4 参与胶原交联,可能与微裂缝形成和骨修复机制有关。初步功能分析显示,与两个对照组相比,患有 LOXL4 变异的非亲缘关系患者的皮肤成纤维细胞衍生的成骨细胞表达的 I 型胶原蛋白和弹性蛋白较少,而成骨分化和矿化则有所增强。总之,这种 LOXL4 变异可能是 AFF 易感性的基础,其原因可能是胶原代谢异常导致股骨微损伤的形成增加或微裂缝的愈合受到影响。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Journal of Bone and Mineral Research
Journal of Bone and Mineral Research 医学-内分泌学与代谢
CiteScore
11.30
自引率
6.50%
发文量
257
审稿时长
2 months
期刊介绍: The Journal of Bone and Mineral Research (JBMR) publishes highly impactful original manuscripts, reviews, and special articles on basic, translational and clinical investigations relevant to the musculoskeletal system and mineral metabolism. Specifically, the journal is interested in original research on the biology and physiology of skeletal tissues, interdisciplinary research spanning the musculoskeletal and other systems, including but not limited to immunology, hematology, energy metabolism, cancer biology, and neurology, and systems biology topics using large scale “-omics” approaches. The journal welcomes clinical research on the pathophysiology, treatment and prevention of osteoporosis and fractures, as well as sarcopenia, disorders of bone and mineral metabolism, and rare or genetically determined bone diseases.
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