title: A novel erythrocytosis-associated PHD2 mutation suggests the location of a HIF binding groove.
abstract: The molecular basis of the erythrocytosis group of red cell disorders is incompletely defined. Some cases are due to dysregulation of erythropoietin (Epo) synthesis. The hypoxia inducible transcription factor (HIF) tightly regulates Epo synthesis. HIF in turn is regulated through its alpha subunit, which under normoxic conditions is hydroxylated on specific prolines and targeted for degradation by the von Hippel Lindau (VHL) protein. Several mutations in VHL have been reported in erythrocytosis, but only 1 mutation in the HIF prolyl hydroxylase PHD2 (prolyl hydroxylase domain protein 2) has been described. Here, we report a novel PHD2 mutation, Arg371His, which causes decreased HIF binding, HIF hydroxylase, and HIF inhibitory activities. In the tertiary structure of PHD2, Arg371 lies close to the previously described Pro317Arg mutation site. These findings substantiate PHD2 as a critical enzyme controlling HIF and therefore Epo in humans, and furthermore suggest the location of an active site groove in PHD2 that binds HIF.
authors.affiliation: Department of Haematology, Belfast City Hospital, Belfast, United Kingdom. melanie.percy@belfasttrust.hscni.net
authors.forename: Melanie J
authors.initials: MJ
authors.lastname: Percy
authors.forename: Paul W
authors.initials: PW
authors.lastname: Furlow
authors.forename: Philip A
authors.initials: PA
authors.lastname: Beer
authors.forename: Terence R J
authors.initials: TR
authors.lastname: Lappin
authors.forename: Mary Frances
authors.initials: MF
authors.lastname: McMullin
authors.forename: Frank S
authors.initials: FS
authors.lastname: Lee
mesh_terms: D000328:Adult; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics* / Q000378:metabolism; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D008297:Male; D009154:Mutation / Q000235:genetics*; D011086:Polycythemia / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D011393:Procollagen-Proline Dioxygenase / Q000235:genetics* / Q000378:metabolism; D017467:Receptors, Erythropoietin / Q000235:genetics / Q000378:metabolism; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics / Q000378:metabolism
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017467:Receptors, Erythropoietin; C490190:EGLN1 protein, human; D011393:Procollagen-Proline Dioxygenase; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D051794:Von Hippel-Lindau Tumor Suppressor Protein