Center of Translational Medicine, Central Hospital of Zibo, Shandong University, Zibo, China.
Department of Neurosurgery, Central Hospital of Zibo, Shandong University, Zibo, China.
Ann Hum Genet. 2020 Jan;84(1):92-96. doi: 10.1111/ahg.12344. Epub 2019 Jul 26.
Osteoporosis is a complex bone metabolic disorder. Genetic factors play an important role in the development of osteoporosis. Mutations in more than 15 genes have been identified to be responsible for osteoporosis to date. Most recently, the gene PLS3 encoding plastin 3 was recognized to be involved in X-linked osteoporosis. Here, we recruited a four-generation Chinese family with X-linked osteoporosis, which had its onset in childhood and was characterized by peripheral fractures and low bone mineral density. All affected individuals shared a nonsense variant (c.244C > T) in exon 4 of PLS3 on Xq23. The variant in affected individuals segregated with the osteoporosis phenotype. By restriction analysis using Dra I, this variant was confirmed in all affected individuals but was not detected in unaffected family members or in 100 unrelated Chinese male controls. The variant was predicted to cause a premature termination of messenger RNA (mRNA) translation (p.Gln82*). The mutant mRNA degraded via the mechanism of "nonsense-mediated mRNA decay." In the present study, we identified a novel nonsense variant of PLS3 in early-onset X-linked osteoporosis and provided a novel insight into the molecular mechanism underlying the pathogenesis of osteoporosis.
骨质疏松症是一种复杂的骨骼代谢紊乱。遗传因素在骨质疏松症的发展中起着重要作用。迄今为止，已经确定了 15 多个基因突变与骨质疏松症有关。最近，编码 plastin 3 的基因 PLS3 被认为与 X 连锁骨质疏松症有关。在这里，我们招募了一个有四代人的中国 X 连锁骨质疏松症家族，其发病始于儿童期，表现为外周骨折和低骨密度。所有受影响的个体在 Xq23 上的 PLS3 外显子 4 中都共享一个无意义变异（c.244C>T）。该变异在受影响的个体中与骨质疏松表型分离。通过使用 Dra I 的限制性分析，该变异在所有受影响的个体中均被证实，但在未受影响的家庭成员或 100 名无关的中国男性对照中未检测到。该变异预计会导致信使 RNA（mRNA）翻译的提前终止（p.Gln82*）。突变的 mRNA 通过“无意义介导的 mRNA 降解”机制降解。在本研究中，我们在早发性 X 连锁骨质疏松症中鉴定出 PLS3 的一种新型无意义变异，并为骨质疏松症发病机制的分子机制提供了新的见解。
