Birt Hogg-Dube Syndrome-Associated FLCN Mutations Disrupt Protein Stability

M S Nahorski, A Reiman, D H K Lim, R K Nookala, L Seabra, X H Lu, J Fenton, U Boora, M Nordenskjold, F Latif, Laurence D Hurst, E R Maher

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Germline mutations in the FLCN gene cause Birt-Hogg-Dube 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. Hum Mutat 32:921-929, 2011.
Original languageEnglish
Pages (from-to)921-929
Number of pages9
JournalHuman Mutation
Volume32
Issue number8
DOIs
Publication statusPublished - Aug 2011

Fingerprint

Birt-Hogg-Dube Syndrome
Estrone
Protein Stability
Sequence Deletion
Mutation
Genes
Neoplasms
Germ-Line Mutation
Pneumothorax
Codon
Computer Simulation
Sequence Analysis
Virulence
Growth
Proteins

Keywords

  • protein stability
  • folliculin
  • molecular evolution
  • Birt Hogg Dube
  • FLCN

Cite this

Nahorski, M. S., Reiman, A., Lim, D. H. K., Nookala, R. K., Seabra, L., Lu, X. H., ... Maher, E. R. (2011). Birt Hogg-Dube Syndrome-Associated FLCN Mutations Disrupt Protein Stability. Human Mutation, 32(8), 921-929. https://doi.org/10.1002/humu.21519

Birt Hogg-Dube Syndrome-Associated FLCN Mutations Disrupt Protein Stability. / Nahorski, M S; Reiman, A; Lim, D H K; Nookala, R K; Seabra, L; Lu, X H; Fenton, J; Boora, U; Nordenskjold, M; Latif, F; Hurst, Laurence D; Maher, E R.

In: Human Mutation, Vol. 32, No. 8, 08.2011, p. 921-929.

Research output: Contribution to journalArticle

Nahorski, MS, Reiman, A, Lim, DHK, Nookala, RK, Seabra, L, Lu, XH, Fenton, J, Boora, U, Nordenskjold, M, Latif, F, Hurst, LD & Maher, ER 2011, 'Birt Hogg-Dube Syndrome-Associated FLCN Mutations Disrupt Protein Stability', Human Mutation, vol. 32, no. 8, pp. 921-929. https://doi.org/10.1002/humu.21519
Nahorski MS, Reiman A, Lim DHK, Nookala RK, Seabra L, Lu XH et al. Birt Hogg-Dube Syndrome-Associated FLCN Mutations Disrupt Protein Stability. Human Mutation. 2011 Aug;32(8):921-929. https://doi.org/10.1002/humu.21519
Nahorski, M S ; Reiman, A ; Lim, D H K ; Nookala, R K ; Seabra, L ; Lu, X H ; Fenton, J ; Boora, U ; Nordenskjold, M ; Latif, F ; Hurst, Laurence D ; Maher, E R. / Birt Hogg-Dube Syndrome-Associated FLCN Mutations Disrupt Protein Stability. In: Human Mutation. 2011 ; Vol. 32, No. 8. pp. 921-929.
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