Birt Hogg-Dubé syndrome-associated FLCN mutations disrupt protein stability

Michael S Nahorski, Anne Reiman, Derek H K Lim, Ravi K Nookala, Laurence Seabra, Xiaohong Lu, Janine Fenton, Uncaar Boora, Magnus Nordenskjöld, Farida Latif, Laurence D Hurst, Eamonn R Maher

Research output: Contribution to journalArticlepeer-review

33 Citations (Scopus)


Germline mutations in the FLCN gene cause Birt-Hogg-Dubé syndrome, familial spontaneous pneumothorax, or apparently nonsyndromic inherited RCC. The vast majority of reported FLCN mutations are predicted to result in a truncated/absent gene product and so infrequent missense and inframe-deletion (IFD) FLCN mutations might indicate critical functional domains. To investigate this hypothesis we (1) undertook an in silico evolutionary analysis of the FLCN sequence and (2) investigated in vitro the functional effects of naturally occurring FLCN missense/IFD mutations. The folliculin protein sequence evolved more slowly and was under stronger purifying selection than the average gene, most notably at a region between codons 100 and 230. Pathogenic missense and IFD FLCN mutations that impaired folliculin tumor suppressor function significantly disrupted the stability of the FLCN gene product but two missense substitutions initially considered to be putative mutations did not impair protein stability, growth suppression activity, or intracellular localization of folliculin. These findings are consistent with the distribution of FLCN mutations throughout the coding sequence, and suggest that multiple protein domains contribute to folliculin stability and tumor suppressor activity. In vitro assessment of protein stability and tumor suppressor activity provides a practical strategy for assessing the pathogenicity of potential FLCN mutations.

Original languageEnglish
Pages (from-to)921-929
Number of pages9
JournalHuman Mutation
Issue number8
Publication statusPublished - Aug 2011


  • Birt-Hogg-Dube Syndrome
  • Cell Line, Tumor
  • Cell Proliferation
  • Computational Biology
  • Evolution, Molecular
  • Gene Order
  • Humans
  • Intracellular Space
  • Models, Statistical
  • Mutation
  • Protein Stability
  • Protein Transport
  • Proto-Oncogene Proteins
  • Tumor Suppressor Proteins
  • Journal Article
  • Research Support, Non-U.S. Gov't


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