title: A novel EPAS1/HIF2A germline mutation in a congenital polycythemia with paraganglioma.
abstract: Congenital polycythemias have diverse etiologies, including mutations in the hypoxia sensing pathway. These include HIF2A at exon 12, VHL gene (Chuvash polycythemia), and PHD2 mutations, which in one family was also associated with recurrent pheochromocytoma/paraganglioma (PHEO/PGL). Over the past two decades, we have studied seven unrelated patients with sporadic congenital polycythemia who subsequently developed PHEO/PGL with, until now, no discernible molecular basis. We now report a polycythemic patient with a novel germline HIF2A (F374Y) (exon 9) mutation, inherited from his mother, who developed PHEO/PGL. We show that this is a gain-of-function mutation and demonstrate no loss-of-heterozygosity or additional somatic mutation of HIF2A in the tumor, indicating HIF2A (F374Y) may be predisposing rather than causative of PHEO/PGL. This report, in view of two other concomitantly reported PHEO/PGL patients with somatic mutations of HIF2A and polycythemia, underscores the PHEO/PGL-promoting potential of mutations of HIF2A that alone are not sufficient for PHEO/PGL development.
authors.affiliation: Hematology Division, University of Utah School of Medicine and VAH, 30N 1900E, 5C402, Salt Lake City, UT 84132, USA.
authors.forename: Felipe R
authors.initials: FR
authors.lastname: Lorenzo
authors.forename: Chunzhang
authors.initials: C
authors.lastname: Yang
authors.forename: Mark
authors.initials: M
authors.lastname: Ng Tang Fui
authors.forename: Hariprasad
authors.initials: H
authors.lastname: Vankayalapati
authors.forename: Zhengping
authors.initials: Z
authors.lastname: Zhuang
authors.forename: Thanh
authors.initials: T
authors.lastname: Huynh
authors.forename: Mathis
authors.initials: M
authors.lastname: Grossmann
authors.forename: Karel
authors.initials: K
authors.lastname: Pacak
authors.forename: Josef T
authors.initials: JT
authors.lastname: Prchal
mesh_terms: D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D001483:Base Sequence; D051792:Basic Helix-Loop-Helix Proteins / Q000737:chemistry / Q000235:genetics*; D005260:Female; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010235:Paraganglioma / Q000150:complications* / Q000235:genetics*; D011086:Polycythemia / Q000150:complications* / Q000151:congenital / Q000235:genetics*; D011487:Protein Conformation; D016415:Sequence Alignment; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D000099162:Endothelial PAS Domain-Containing Protein 1