PDF(Pubmed)
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.
CONCLUSIONS: Our data indicate impaired bone resorption as the underlying mechanism of this rare osteosclerosis, implicating ALOX5 pathogenic variants as potential etiological factors.
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.
CONCLUSIONS: Our data indicate impaired bone resorption as the underlying mechanism of this rare osteosclerosis, implicating ALOX5 pathogenic variants as potential etiological factors.
摘要：
背景：骨组织稳态依赖于骨形成成骨细胞和骨吸收破骨细胞的协调活动。骨固缩症被认为是一种独特的罕见硬化性骨骼疾病，具有未阐明的病理生理学和可能的常染色体显性传播。然而,因果基因是未知的。
方法：我们提供了一个病例报告，包括临床评估，影像学检查,和全外显子组测序分析，补充功能体外实验。
结果：这例新的骨内缩与一个错义ALOX5变异体有关，该变异体预测会诱导蛋白质错误折叠和蛋白酶体降解。转染实验表明，该变体与硼替佐米蛋白酶体抑制恢复的蛋白质水平降低有关。同样，基因表达分析表明，突变基因与RANKL/OPG比值降低有关，这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受损是这种罕见骨硬化的潜在机制，提示ALOX5致病变异是潜在的病因。
方法：我们提供了一个病例报告，包括临床评估，影像学检查,和全外显子组测序分析，补充功能体外实验。
结果：这例新的骨内缩与一个错义ALOX5变异体有关，该变异体预测会诱导蛋白质错误折叠和蛋白酶体降解。转染实验表明，该变体与硼替佐米蛋白酶体抑制恢复的蛋白质水平降低有关。同样，基因表达分析表明，突变基因与RANKL/OPG比值降低有关，这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受损是这种罕见骨硬化的潜在机制，提示ALOX5致病变异是潜在的病因。
