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

Research output: Contribution to journalArticle


  • Michael Nahorski
  • RK Nookala
  • L Seabra
  • Janine Fenton
  • Uncaar Boora
  • M Nordenskjöld
  • LD Hurst

Colleges, School and Institutes


Germline mutations in the FLCN gene cause Birt-Hogg-Dubé syndrome, familial spontaneous pneumothorax or apparently non-syndromic 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 (a) undertook an in silico evolutionary analysis of the FLCN sequence and (b) 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 tumour 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 localisation 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 tumour suppressor activity. In vitro assessment of protein stability and tumour suppressor activity provides a practical strategy for assessing the pathogenicity of potential FLCN mutations. © 2011 Wiley-Liss, Inc.


Original languageEnglish
JournalHuman Mutation
Publication statusPublished - 28 Apr 2011