骨质疏松症与影响 RANKL 通路的新型 ALOX5 变异有关。

IF 1.5 4区 医学 Q4 GENETICS & HEREDITY
Jose L Fernandez-Luna, José L Hernández, Soraya Curiel-Olmo, Néstor A Martínez-Amador, Ana I Vega, Remedios Quirce, Santiago Montes-Moreno, Olga Gutierrez, Alvaro Del Real, Carolina Sañudo, Jose A Riancho
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引用次数: 0

摘要

背景:骨组织的平衡依赖于骨形成的成骨细胞和骨吸收的破骨细胞的协调活动。骨硬化症被认为是一种独特的罕见硬化性骨骼疾病,其病理生理学尚未阐明,可能为常染色体显性遗传。然而,其致病基因尚不清楚:我们提交了一份病例报告,其中包括临床评估、影像学研究和全外显子组测序分析,并辅以体外功能实验:结果:这一新的骨质疏松症病例与一个错义 ALOX5 变体有关,该变体被认为可诱导蛋白质错误折叠和蛋白酶体降解。转染实验表明,用硼替佐米抑制蛋白酶体可恢复蛋白水平。同样,基因表达分析表明,突变基因与 RANKL/OPG 比率降低有关,而 RANKL/OPG 比率是破骨细胞前体分化的关键驱动因素:结论:我们的数据表明,骨吸收障碍是这种罕见骨硬化症的基本机制,ALOX5致病变体是潜在的致病因素。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Osteomesopyknosis associated with a novel ALOX5 variant that impacts the RANKL pathway.

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.

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来源期刊
Molecular Genetics & Genomic Medicine
Molecular Genetics & Genomic Medicine Biochemistry, Genetics and Molecular Biology-Genetics
CiteScore
4.20
自引率
0.00%
发文量
241
审稿时长
14 weeks
期刊介绍: Molecular Genetics & Genomic Medicine is a peer-reviewed journal for rapid dissemination of quality research related to the dynamically developing areas of human, molecular and medical genetics. The journal publishes original research articles covering findings in phenotypic, molecular, biological, and genomic aspects of genomic variation, inherited disorders and birth defects. The broad publishing spectrum of Molecular Genetics & Genomic Medicine includes rare and common disorders from diagnosis to treatment. Examples of appropriate articles include reports of novel disease genes, functional studies of genetic variants, in-depth genotype-phenotype studies, genomic analysis of inherited disorders, molecular diagnostic methods, medical bioinformatics, ethical, legal, and social implications (ELSI), and approaches to clinical diagnosis. Molecular Genetics & Genomic Medicine provides a scientific home for next generation sequencing studies of rare and common disorders, which will make research in this fascinating area easily and rapidly accessible to the scientific community. This will serve as the basis for translating next generation sequencing studies into individualized diagnostics and therapeutics, for day-to-day medical care. Molecular Genetics & Genomic Medicine publishes original research articles, reviews, and research methods papers, along with invited editorials and commentaries. Original research papers must report well-conducted research with conclusions supported by the data presented.
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