RT Journal Article
T1 Functional Characterization of a GGPPS Variant Identified in Atypical Femoral Fracture Patients and Delineation of the Role of GGPPS in Bone-Relevant Cell Types.
A1 Roca-Ayats, Neus
A1 Ng, Pei Ying
A1 Garcia-Giralt, Natalia
A1 Falco-Mascaro, Maite
A1 Cozar, Mónica
A1 Abril, Josep Francesc
A1 Quesada Gomez, Jose Manuel
A1 Prieto-Alhambra, Daniel
A1 Nogues, Xavier
A1 Dunford, James E
A1 Russell, R Graham
A1 Baron, Roland
A1 Grinberg, Daniel
A1 Balcells, Susana
A1 Diez-Perez, Adolfo
K1 Atypical femoral fractures
K1 Bisphosphonates
K1 GGPS1
K1 WES
AB Atypical femoral fractures (AFFs) are a rare but potentially devastating event, often but not always linked to bisphosphonate (BP) therapy. The pathogenic mechanisms underlying AFFs remain obscure, and there are no tests available that might assist in identifying those at high risk of AFF. We previously used exome sequencing to explore the genetic background of three sisters with AFFs and three additional unrelated AFF cases, all previously treated with BPs. We detected 37 rare mutations (in 34 genes) shared by the three sisters. Notably, we found a p.Asp188Tyr mutation in the enzyme geranylgeranyl pyrophosphate synthase, a component of the mevalonate pathway, which is critical to osteoclast function and is inhibited by N-BPs. In addition, the CYP1A1 gene, responsible for the hydroxylation of 17β-estradiol, estrone, and vitamin D, was also mutated in all three sisters and one unrelated patient. Here we present a detailed list of the variants found and report functional analyses of the GGPS1 p.Asp188Tyr mutation, which showed a severe reduction in enzyme activity together with oligomerization defects. Unlike BP treatment, this genetic mutation will affect all cells in the carriers. RNAi knockdown of GGPS1 in osteoblasts produced a strong mineralization reduction and a reduced expression of osteocalcin, osterix, and RANKL, whereas in osteoclasts, it led to a lower resorption activity. Taken together, the impact of the mutated GGPPS and the relevance of the downstream effects in bone cells make it a strong candidate for AFF susceptibility. We speculate that other genes such as CYP1A1 might be involved in AFF pathogenesis, which remains to be functionally proved. The identification of the genetic background for AFFs provides new insights for future development of novel risk assessment tools. © 2018 American Society for Bone and Mineral Research.
PB Oxford University Press
YR 2018
FD 2018-08-26
LK http://hdl.handle.net/10668/12910
UL http://hdl.handle.net/10668/12910
LA en
NO Roca-Ayats N, Ng PY, Garcia-Giralt N, Falcó-Mascaró M, Cozar M, Abril JF, et al. Functional Characterization of a GGPPS Variant Identified in Atypical Femoral Fracture Patients and Delineation of the Role of GGPPS in Bone-Relevant Cell Types. J Bone Miner Res. 2018 Dec;33(12):2091-2098
NO We thank the patients for their kind participation. Funds for the study include grants SAF2014-56562R, SAF2016-75948-R (Spanish MINECO), PI12/02315 (FIS, ISCII), 2014SGR932 (Cata lan Government), and CIBERER (U720). This work was also supported by the Centro de Investigacion Biomedica en Red en Fragilidad y Envejecimiento Saludable (CIBERFES; B16/10/00245) and FEDER funds. JED was supported by the NIHR Biomedical Research Centre, Oxford, UK. NR is recipient of an FPU predoctoral fellowship from the Spanish Ministerio de Educacion Cultura y Deporte. The work was also supported by a grant from the US government, NIH, NIAMS (R01 AR062054) to RB
DS RISalud
RD Apr 7, 2025