Birt-Hogg-Dube syndrome is a novel ciliopathy

Hum Mol Genet. 2013 Nov 1;22(21):4383-97. doi: 10.1093/hmg/ddt288. Epub 2013 Jun 19.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Birt-Hogg-Dube Syndrome / genetics
  • Birt-Hogg-Dube Syndrome / physiopathology*
  • Cell Line
  • Cell Polarity
  • Cell Proliferation
  • Centrosome / physiology
  • Cilia / pathology
  • Cilia / physiology*
  • Humans
  • Kidney / physiology
  • Microtubules / physiology
  • Molecular Sequence Data
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins / metabolism*
  • Sequence Analysis, DNA
  • Tumor Suppressor Proteins / genetics*
  • Tumor Suppressor Proteins / metabolism*
  • Wnt Signaling Pathway

Substances

  • FLCN protein, human
  • Proto-Oncogene Proteins
  • Tumor Suppressor Proteins