Department of Dermatology and GROW School for Oncology and Developmental Biology.
Hum Mol Genet. 2013 Nov 1;22(21):4383-97. doi: 10.1093/hmg/ddt288. Epub 2013 Jun 19.
Birt-Hogg-Dubé (BHD) syndrome is an autosomal dominant disorder where patients are predisposed to kidney cancer, lung and kidney cysts and benign skin tumors. BHD is caused by heterozygous mutations affecting folliculin (FLCN), a conserved protein that is considered a tumor suppressor. Previous research has uncovered multiple roles for FLCN in cellular physiology, yet it remains unclear how these translate to BHD lesions. Since BHD manifests hallmark characteristics of ciliopathies, we speculated that FLCN might also have a ciliary role. Our data indicate that FLCN localizes to motile and non-motile cilia, centrosomes and the mitotic spindle. Alteration of FLCN levels can cause changes to the onset of ciliogenesis, without abrogating it. In three-dimensional culture, abnormal expression of FLCN disrupts polarized growth of kidney cells and deregulates canonical Wnt signalling. Our findings further suggest that BHD-causing FLCN mutants may retain partial functionality. Thus, several BHD symptoms may be due to abnormal levels of FLCN rather than its complete loss and accordingly, we show expression of mutant FLCN in a BHD-associated renal carcinoma. We propose that BHD is a novel ciliopathy, its symptoms at least partly due to abnormal ciliogenesis and canonical Wnt signalling.
Birt-Hogg-Dubé（BHD）综合征是一种常染色体显性遗传病，患者易患肾癌、肺和肾囊肿以及良性皮肤肿瘤。BHD 是由影响卵泡抑素（FLCN）的杂合突变引起的，FLCN 是一种保守蛋白，被认为是一种肿瘤抑制因子。先前的研究揭示了 FLCN 在细胞生理学中的多种作用，但尚不清楚这些作用如何转化为 BHD 病变。由于 BHD 表现出典型的纤毛病特征，我们推测 FLCN 也可能具有纤毛作用。我们的数据表明，FLCN 定位于能动和非能动纤毛、中心体和有丝分裂纺锤体。FLCN 水平的改变会导致纤毛发生的起始发生变化，但不会使其完全消失。在三维培养中，FLCN 的异常表达会破坏肾脏细胞的极化生长，并使经典 Wnt 信号通路失调。我们的研究结果进一步表明，导致 BHD 的 FLCN 突变体可能保留部分功能。因此，一些 BHD 症状可能是由于 FLCN 水平异常而不是其完全缺失引起的，因此，我们在 BHD 相关的肾细胞癌中显示了突变型 FLCN 的表达。我们提出 BHD 是一种新型纤毛病，其症状至少部分是由于异常纤毛发生和经典 Wnt 信号通路引起的。
