Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
Division of Pulmonary Medicine, Boston Children's Hospital, Boston, Massachusetts.
Semin Respir Crit Care Med. 2020 Apr;41(2):247-255. doi: 10.1055/s-0040-1708500. Epub 2020 Apr 12.
Birt-Hogg-Dubé (BHD) syndrome is an autosomal dominant disorder caused by germline loss-of-function mutations in gene (FLCN). BHD is characterized by lower lobe-predominant pulmonary cysts with risk of pneumothorax, benign skin tumors (fibrofolliculomas), and renal cell carcinoma, often of an unusual chromophobe/oncocytic hybrid histology. The FLCN protein functions in multiple signaling and metabolic pathways including positive regulation of mechanistic target of rapamycin complex 1 (mTORC1) activity via FLCN's GTPase (GAP) activity for Rag C, positive regulation of Wnt signaling (in mesenchymal cells), and negative regulation of TFE3 nuclear localization. Therefore, FLCN-deficient cells are predicted to have reduced mTORC1 and Wnt activity and enhanced TFE3 activity. Folliculin also has functions in autophagy, mitochondrial biogenesis, cell-cell adhesion, 5' AMP activated protein kinase activity, and other pathways. The specific contributions of these pathways to the lung manifestations of BHD are largely unknown. This review is focused on the pulmonary manifestations of BHD, highlighting selected recent advances in elucidating the cellular functions of FLCN and current hypotheses related to the pathogenesis of cystic lung disease in BHD, including the "stretch hypothesis." We also discuss important knowledge gaps in the field, including the genetic, cellular and physical mechanisms of cyst pathogenesis, and the timing of cyst initiation, which may occur during lung development.
Birt-Hogg-Dubé（BHD）综合征是一种常染色体显性遗传病，由基因（FLCN）的种系失活突变引起。BHD 的特征是下叶为主的肺囊肿，伴有气胸风险、良性皮肤肿瘤（纤维毛囊瘤）和肾细胞癌，通常为不常见的嗜铬细胞瘤/嗜酸细胞混合组织学。FLCN 蛋白在多种信号和代谢途径中发挥作用，包括通过 FLCN 的 GTPase（GAP）活性正向调节雷帕霉素复合物 1（mTORC1）的活性，从而正向调节 Rag C，正向调节 Wnt 信号（在间充质细胞中），以及负向调节 TFE3 核定位。因此，预计 FLCN 缺陷细胞的 mTORC1 和 Wnt 活性降低，TFE3 活性增强。滤泡素还具有自噬、线粒体生物发生、细胞间黏附、5'AMP 激活蛋白激酶活性和其他途径的功能。这些途径对 BHD 肺部表现的具体贡献在很大程度上尚不清楚。本文综述了 BHD 的肺部表现，重点介绍了阐明 FLCN 细胞功能的最新进展以及与 BHD 囊性肺部疾病发病机制相关的当前假说，包括“拉伸假说”。我们还讨论了该领域的重要知识空白，包括囊肿发病的遗传、细胞和物理机制，以及囊肿起始的时间，可能发生在肺发育过程中。
