Novel HIF2A mutations disrupt oxygen sensing, leading to polycythemia, paragangliomas, and somatostatinomas.
Hypoxia-inducible factors (HIFs) control the cellular response to hypoxia and, when dysregulated, contribute to tumorigenesis. Previously, we identified 2 gain-of-function somatic mutations in patients presenting with multiple paragangliomas or somatostatinomas, and polycythemia. Here, we report 2 additional unique HIF2A mutations, which disrupt the hydroxylation domain recognized by prolyl hydroxylase domain-2 containing protein, leading to stabilization of HIF-2α and increased expression of hypoxia-related genes.
Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20894, USA.
Chunzhang
C
Yang
Michael G
MG
Sun
Joey
J
Matro
Thanh T
TT
Huynh
Shervin
S
Rahimpour
Josef T
JT
Prchal
Ronald
R
Lechan
Russell
R
Lonser
Karel
K
Pacak
Zhengping
Z
Zhuang
D000008:Abdominal Neoplasms / Q000235:genetics / Q000378:metabolism; D000595:Amino Acid Sequence; D001483:Base Sequence; D051792:Basic Helix-Loop-Helix Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D005260:Female; D006367:HeLa Cells; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation / Q000502:physiology; D010100:Oxygen / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism; D010235:Paraganglioma / Q000235:genetics* / Q000378:metabolism; D010802:Phylogeny; D011086:Polycythemia / Q000235:genetics* / Q000378:metabolism; D013005:Somatostatinoma / Q000235:genetics* / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D010100:Oxygen; D000099162:Endothelial PAS Domain-Containing Protein 1