Erythrocytosis associated with a novel missense mutation in the HIF2A gene

• Published in: Haematologica (Roma) 2010-05, Vol.95 (5), p.829-832
• Main Authors: VAN WIJK, Richard, SUTHERLAND, Scott, VAN WESEL, Annet C. W, HUIZINGA, Eric G, PERCY, Melanie J, BIERINGS, Marc, LEE, Frank S
• Format: Article
• Language: English
• Subjects: Adolescent; Basic Helix-Loop-Helix Transcription Factors - chemistry; Basic Helix-Loop-Helix Transcription Factors - genetics; Biological and medical sciences; Brief Reports; Diseases of red blood cells; Female; Hematologic and hematopoietic diseases; Humans; Medical sciences; Mutation, Missense - genetics; Polycythemia - diagnosis; Polycythemia - genetics; Polycythemias
• ISSN: 0390-6078; 1592-8721
• DOI: 10.3324/haematol.2009.017582

The ERYTHROPOIETIN (EPO) gene is regulated by the transcription factor Hypoxia Inducible Factor-alpha (HIF-alpha). In this pathway, Prolyl Hydroxylase Domain protein 2 (PHD2) hydroxylates two prolyl residues in HIF-alpha, which in turn promotes HIF-alpha degradation by the von Hippel Lindau (VHL) protein. Evidence that HIF-2alpha is the important isoform for EPO regulation in humans comes from the recent observation that mutations in the HIF2A gene are associated with cases of erythrocytosis. We report here a new erythrocytosis-associated mutation, p.Asp539Glu, in the HIF2A gene. Similar to all reported cases, the affected residue is in close vicinity and C-terminal to the primary hydroxylation site in HIF-2alpha, Pro531. This mutation, however, is notable in producing a rather subtle amino acid substitution. Nonetheless, we find that this mutation compromises binding of HIF-2alpha to both PHD2 and VHL, and we propose that this mutation is the cause of erythrocytosis in this individual.