Unique gender-dependent serum microRNA profile in PLS3 osteoporosis in PLS3 gene related osteoporosis. Unique gender-dependent serum microRNA profile in PLS3 osteoporosis in PLS3 gene related osteoporosis

Plastin 3 (PLS3), encoded by PLS3, is a newly recognized regulator of bone metabolism and mutations in the encoding gene result in severe childhood-onset osteoporosis. Since an X chromosomal gene, PLS3 mutation-positive males are typically more severely affected while females portray normal to increased skeletal fragility. Despite the severe skeletal pathology, conventional metabolic bone markers tend to be normal and are thus insufficient in diagnosing or monitoring patients. Our study aimed to explore serum microRNA (miRNA) concentrations in subjects with defective PLS3 function to identify novel markers that could differentiate subjects according to mutation status and give insight into the molecular mechanisms by which PLS3 regulates skeletal health. We analyzed fasting serum samples for a custom-designed panel comprising 192 miRNAs in 15 mutation-positive (5 males, age range 8–76 years, median 41 years) and 14 mutation-negative (6 males, 8–69 years, 40 years) subjects from four Finnish families with different PLS3 mutations. We identified a unique miRNA expression profile in the mutation-positive subjects with seven significantly up- or downregulated miRNAs (miR-93-3p, miR-532-3p, miR-133a-3p, miR-301b-3p, miR-181c-5p, miR-203a-3p, miR-590-3p; p-values 0.004–0.044). Overall design: We analyzed fasting serum samples for a custom-designed panel comprising 192 miRNAs in 15 mutation-positive (5 males, age range 8–76 years, median 41 years) and 14 mutation-negative (6 males, 8–69 years, 40 years) subjects from four Finnish families with different PLS3 mutations.

丝束蛋白3（Plastin 3, PLS3）由PLS3基因编码，是新近被鉴定的骨代谢调控因子，其编码基因突变可引发儿童期起病的重度骨质疏松症。由于该基因属于X染色体连锁基因，携带PLS3突变的男性通常临床症状更为严重，而女性则表现为骨骼脆性正常甚至升高。尽管此类患者存在严重的骨骼病理异常，常规骨代谢生化标志物往往处于正常水平，因此无法用于该类患者的诊断或病情监测。本研究旨在探究PLS3功能缺陷受试者的血清微小核糖核酸（microRNA, miRNA）表达水平，以期识别可依据突变状态区分受试者的新型标志物，并阐明PLS3调控骨骼健康的分子机制。我们对来自4个携带不同PLS3突变的芬兰家系的15例PLS3突变阳性受试者（5例男性，年龄范围8~76岁，中位年龄41岁）及14例突变阴性受试者（6例男性，年龄范围8~69岁，中位年龄40岁）的空腹血清样本进行了检测，采用定制的192种miRNA检测组合。本研究在突变阳性受试者中鉴定出独特的miRNA表达谱，共7种miRNA存在显著上调或下调（miR-93-3p、miR-532-3p、miR-133a-3p、miR-301b-3p、miR-181c-5p、miR-203a-3p、miR-590-3p；P值范围0.004~0.044）。整体实验设计：我们对来自4个携带不同PLS3突变的芬兰家系的15例PLS3突变阳性受试者（5例男性，年龄范围8~76岁，中位年龄41岁）及14例突变阴性受试者（6例男性，年龄范围8~69岁，中位年龄40岁）的空腹血清样本进行了检测，采用定制的192种miRNA检测组合。