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Osteomesopyknosis associated with a novel ALOX5 variant that impacts the RANKL pathway

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.

 Authorship: Fernandez-Luna J.L., Hernández J.L., Curiel-Olmo S., Martínez-Amador N.A., Vega A.I., Quirce R., Montes-Moreno S., Gutierrez O., del Real A., Sañudo C., Riancho J.A.,

 Fuente: Molecular Genetics and Genomic Medicine, 2024, 12, e2471

 Publisher: Wiley-Blackwell

 Year of publication: 2024

 No. of pages: 8

 Publication type: Article

 DOI: 10.1002/mgg3.2471

 ISSN: 2324-9269

 Publication Url: https://doi.org/10.1002/mgg3.2471

Authorship

JOSE LUIS FERNANDEZ LUNA

SORAYA CURIEL DEL OLMO

MARTÍNEZ-AMADOR, NÉSTOR A.

VEGA, ANA I.

GUTIÉRREZ, OLGA

ÁLVARO DEL REAL BOLT

MARIA CAROLINA SAÑUDO CAMPO