Departments of Pathology and Radiology, Albert Einstein College of Medicine and Montefiore Medical Center, New York City, New York.
Clin Genet. 2018 Feb;93(2):412-416. doi: 10.1111/cge.13165. Epub 2017 Dec 26.
Filamin B (FLNB) functions as a switch that can affect chrondrocyte development and endochondral bone formation through a series of signaling molecules and transcription factors that also affect Sertoli cell development. Here, we report a subject with a novel skeletal dysplasia and co-existing 46,XY gonadal dysgenesis and biallelic mutations in FLNB. Whole exome sequencing was performed to identify mutations. Quantitative polymerase chain reaction (qPCR) and flow variant assays were performed to quantify RNA, proteins and phosphorylated proteins. The TOPFLASH reporter was performed to quantify β-catenin activity. Mutations were identified in the FLNB gene (FLNB:p.F964L, FLNB:p.A1577V). These mutations increased binding of FLNB protein to the MAP3K1 and RAC1 signal transduction complex and activated β-catenin and had different effects on phosphorylation of MAP kinase pathway intermediates and SOX9 expression. Direct activation of β-catenin through the FLNB-MAP3K1-RAC1 complex by FLNB mutations is a novel mechanism for causing 46,XY gonadal dysgenesis. The mechanism of action varies from those reported previously for loss of function mutations in SOX9 and gain-of-function mutations in MAP3K1.
细丝蛋白 B（FLNB）作为一种开关，可通过一系列信号分子和转录因子影响软骨细胞发育和软骨内骨形成，这些信号分子和转录因子也影响睾丸支持细胞的发育。在这里，我们报道了一个具有新型骨骼发育不良和共存 46,XY 性腺发育不全的个体，并在 FLNB 中存在双等位基因突变。进行全外显子组测序以鉴定突变。进行定量聚合酶链反应（qPCR）和流式变体分析以定量 RNA、蛋白质和磷酸化蛋白质。进行 TOPFLASH 报告以定量 β-连环蛋白活性。在 FLNB 基因中鉴定出突变（FLNB：p.F964L，FLNB：p.A1577V）。这些突变增加了 FLNB 蛋白与 MAP3K1 和 RAC1 信号转导复合物的结合，并激活了 β-连环蛋白，并对 MAP 激酶途径中间产物和 SOX9 表达的磷酸化产生不同的影响。FLNB 突变通过 FLNB-MAP3K1-RAC1 复合物直接激活 β-连环蛋白是导致 46,XY 性腺发育不全的一种新机制。作用机制与以前报道的 SOX9 功能丧失突变和 MAP3K1 获得性功能突变不同。
