The Fowler syndrome-associated protein FLVCR2 is an importer of heme

Mol Cell Biol. 2010 Nov;30(22):5318-24. doi: 10.1128/MCB.00690-10. Epub 2010 Sep 7.


Mutations in FLVCR2, a cell surface protein related by homology and membrane topology to the heme exporter/retroviral receptor FLVCR1, have recently been associated with Fowler syndrome, a vascular disorder of the brain. We previously identified FLVCR2 to function as a receptor for FY981 feline leukemia virus (FeLV). However, the cellular function of FLVCR2 remains unresolved. Here, we report the cellular function of FLVCR2 as an importer of heme, based on the following observations. First, FLVCR2 binds to hemin-conjugated agarose, and binding is competed by free hemin. Second, mammalian cells and Xenopus laevis oocytes expressing FLVCR2 display enhanced heme uptake. Third, heme import is reduced after the expression of FLVCR2-specific small interfering RNA (siRNA) or after the binding of the FY981 FeLV envelope protein to the FLVCR2 receptor. Finally, cells overexpressing FLVCR2 are more sensitive to heme toxicity, a finding most likely attributable to enhanced heme uptake. Tissue expression analysis indicates that FLVCR2 is expressed in a broad range of human tissues, including liver, placenta, brain, and kidney. The identification of a cellular function for FLVCR2 will have important implications in elucidating the pathogenic mechanisms of Fowler syndrome and of phenotypically associated disorders.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biological Transport / physiology
  • Brain Diseases / metabolism
  • Brain Diseases / pathology
  • Cats
  • Cell Line
  • Cricetinae
  • Cricetulus
  • Female
  • Heme / metabolism*
  • Heme / toxicity
  • Humans
  • Membrane Transport Proteins / genetics
  • Membrane Transport Proteins / metabolism*
  • Oocytes / cytology
  • Oocytes / physiology
  • Pregnancy
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Receptors, Virus / genetics
  • Receptors, Virus / metabolism*
  • Syndrome
  • Tissue Distribution
  • Xenopus laevis


  • FLVCR1 protein, human
  • FLVCR2 protein, human
  • Membrane Transport Proteins
  • RNA, Small Interfering
  • Receptors, Virus
  • Heme