1. Osteomesopyknosis associated with a novel ALOX5 variant that impacts the RANKL pathway.
- Author
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Fernandez-Luna JL, Hernández JL, Curiel-Olmo S, Martínez-Amador NA, Vega AI, Quirce R, Montes-Moreno S, Gutierrez O, Del Real A, Sañudo C, and Riancho JA
- Subjects
- Female, Humans, Osteoclasts metabolism, Osteoclasts pathology, Osteosclerosis genetics, Osteosclerosis pathology, Osteosclerosis metabolism, Signal Transduction, Middle Aged, Arachidonate 5-Lipoxygenase genetics, Arachidonate 5-Lipoxygenase metabolism, Mutation, Missense, RANK Ligand metabolism, RANK Ligand genetics
- Abstract
Background: Bone tissue homeostasis relies on the coordinated activity of the bone-forming osteoblasts and bone-resorbing osteoclasts. Osteomesopyknosis is considered a distinctive rare sclerosing skeletal disorder of unelucidated pathophysiology and presumably autosomal dominant transmission. However, the causal genes are unknown., Methods: We present a case report encompassing clinical assessments, imaging studies, and whole-exome sequencing analysis, complemented by functional in vitro experiments., Results: This new case of osteomesopyknosis was associated with a missense ALOX5 variant predicted to induce protein misfolding and proteasomal degradation. Transfection experiments demonstrated that the variant was associated with reduced protein levels restored by proteasomal inhibition with bortezomib. Likewise, gene expression analysis showed that the mutated gene was associated with a decreased RANKL/OPG ratio, which is a critical driver of osteoclast precursor differentiation., Conclusion: Our data indicate impaired bone resorption as the underlying mechanism of this rare osteosclerosis, implicating ALOX5 pathogenic variants as potential etiological factors., (© 2024 The Author(s). Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)
- Published
- 2024
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