FLVCR1 was initially identified as a cell-surface attachment site for feline leukemia virus subgroup C [9], and later identified as a cell surface accumulation which exports heme from the cytosol [6]. A recent study indicates that an isoform of FLVCR1 is located in the mitochondria, the site of the final steps of heme synthesis, and appears to transport heme into the cytosol [2]. FLVCR-mediated heme transport is essential for erythropoiesis. Flvcr1 gene mutations have been identified as the cause of PCARP (posterior column ataxia with retinitis pigmentosa (PCARP) [7].There are three paralogs of FLVCR1 in the human genome.

FLVCR2, most similar to FLVCR1 [4], has been reported to function as a heme importer [3]. In addition, a congenital syndrome of proliferative vasculopathy and hydranencephaly, also known as Fowler's syndrome, is associated with a loss-of-function mutation in FLVCR2 [5].

The functions of the other two members of the SLC49 family, MFSD7 and DIRC2, are unknown, although DIRC2 has been implicated in hereditary renal carcinomas [1].

Non-functional splice alternatives of FLVCR1 have been implicated as a cause of a congenital red cell aplasia, Diamond Blackfan anemia [8].

* Key recommended reading is highlighted with an asterisk

* Khan AA, Quigley JG. (2011) Control of intracellular heme levels: heme transporters and heme oxygenases. Biochim Biophys Acta, 1813 (5): 668-82. [PMID:21238504]

* Khan AA, Quigley JG. (2013) Heme and FLVCR-related transporter families SLC48 and SLC49. Mol Aspects Med, 34 (2-3): 669-82. [PMID:23506900]

Krishnamurthy P, Xie T, Schuetz JD. (2007) The role of transporters in cellular heme and porphyrin homeostasis. Pharmacol Ther, 114 (3): 345-58. [PMID:17368550]

Latunde-Dada GO, Simpson RJ, McKie AT. (2006) Recent advances in mammalian haem transport. Trends Biochem Sci, 31 (3): 182-8. [PMID:16487711]

1. Bodmer D, Eleveld M, Kater-Baats E, Janssen I, Janssen B, Weterman M, Schoenmakers E, Nickerson M, Linehan M, Zbar B et al.. (2002) Disruption of a novel MFS transporter gene, DIRC2, by a familial renal cell carcinoma-associated t(2;3)(q35;q21). Hum Mol Genet, 11 (6): 641-9. [PMID:11912179]

2. Chiabrando D, Marro S, Mercurio S, Giorgi C, Petrillo S, Vinchi F, Fiorito V, Fagoonee S, Camporeale A, Turco E et al.. (2012) The mitochondrial heme exporter FLVCR1b mediates erythroid differentiation. J Clin Invest, 122 (12): 4569-79. [PMID:23187127]

3. Duffy SP, Shing J, Saraon P, Berger LC, Eiden MV, Wilde A, Tailor CS. (2010) The Fowler syndrome-associated protein FLVCR2 is an importer of heme. Mol Cell Biol, 30 (22): 5318-24. [PMID:20823265]

4. Lipovich L, Hughes AL, King MC, Abkowitz JL, Quigley JG. (2002) Genomic structure and evolutionary context of the human feline leukemia virus subgroup C receptor (hFLVCR) gene: evidence for block duplications and de novo gene formation within duplicons of the hFLVCR locus. Gene, 286 (2): 203-13. [PMID:11943475]

5. Meyer E, Ricketts C, Morgan NV, Morris MR, Pasha S, Tee LJ, Rahman F, Bazin A, Bessières B, Déchelotte P et al.. (2010) Mutations in FLVCR2 are associated with proliferative vasculopathy and hydranencephaly-hydrocephaly syndrome (Fowler syndrome). Am J Hum Genet, 86 (3): 471-8. [PMID:20206334]

6. Quigley JG, Yang Z, Worthington MT, Phillips JD, Sabo KM, Sabath DE, Berg CL, Sassa S, Wood BL, Abkowitz JL. (2004) Identification of a human heme exporter that is essential for erythropoiesis. Cell, 118 (6): 757-66. [PMID:15369674]

7. Rajadhyaksha AM, Elemento O, Puffenberger EG, Schierberl KC, Xiang JZ, Putorti ML, Berciano J, Poulin C, Brais B, Michaelides M et al.. (2010) Mutations in FLVCR1 cause posterior column ataxia and retinitis pigmentosa. Am J Hum Genet, 87 (5): 643-54. [PMID:21070897]

8. Rey MA, Duffy SP, Brown JK, Kennedy JA, Dick JE, Dror Y, Tailor CS. (2008) Enhanced alternative splicing of the FLVCR1 gene in Diamond Blackfan anemia disrupts FLVCR1 expression and function that are critical for erythropoiesis. Haematologica, 93 (11): 1617-26. [PMID:18815190]

9. Tailor CS, Willett BJ, Kabat D. (1999) A putative cell surface receptor for anemia-inducing feline leukemia virus subgroup C is a member of a transporter superfamily. J Virol, 73 (8): 6500-5. [PMID:10400745]