A cancer-predisposing "hot spot" mutation of the fumarase gene creates a dominant negative protein

Annalisa Lorenzato, Martina Olivero, Mario Perro, Jean Jacques Brière, Pierre Rustin, Maria Flavia Di Renzo

Research output: Contribution to journalArticlepeer-review

Abstract

The Fumarase (Fumarate Hydratase, FH) is a tumor suppressor gene whose germline heterozygous mutations predispose to hereditary leiomyomatosis and renal cell cancer (HLRCC). The FH gene encodes an enzyme of the Krebs cycle, functioning as a homotetramer and catalyzing the hydration of fumarate to malate. Among the numerous FH mutations reported so far, the R190H missense mutation is the most frequent in HLRCC patients. Here we show the functional analyses of the R190H, in comparison to the better characterized E319Q mutation. We first expressed wild-type and mutated proteins in FH deficient human skin fibroblasts, using lentiviral vectors. The wild-type transgene was able to restore the FH enzymatic activity in cells, while the R190H- and E319Q-FH were not. More interestingly, when the same transgenes were expressed in normal, FH-proficient cells, only the R190H-FH reduced the endogenous FH enzymatic activity. By enforcing the expression of equal amount of wild-type and R190H-FH in the same cell, we showed that the mutated FH protein directly inhibited enzymatic activity by nearly abrogating the FH homotetramer formation. These data demonstrate the dominant negative effect of the R190H missense mutation in the FH gene and suggest that the FH tumor-suppressing activity might be impaired in cells carrying a heterozygous mutation.

Original languageEnglish
Pages (from-to)947-951
Number of pages5
JournalInternational Journal of Cancer
Volume122
Issue number4
DOIs
Publication statusPublished - Feb 15 2008

Keywords

  • Fumarate hydratase
  • Functional assays
  • Hereditary leiomyomatosis and renal cell cancer
  • Missense mutations

ASJC Scopus subject areas

  • Cancer Research
  • Medicine(all)
  • Oncology

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