A schema for sporadic and heritable disease pathogenesis integrating spatiotemporal distribution with the character of genetic variants
Hussam R Alkaissia, Yasemin Coleb, Tara T. Doucet-O’Hareb c d, Jared S. Rosenblume, Zhengping Zhuangf✉, Karel Pacákg h✉
- aNational Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, 20892, USA
- bNeuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
- cCenter for Human Genetics, Clemson University, Greenwood, SC, 29646, USA
- dDepartment of Genetics and Biochemistry, Clemson University, Clemson, SC, 29631, USA
Papers open inside SciRah from the original publisher or repository; SciRah never hosts them.
Abstract
The interest in hypoxia-inducible factors (HIFs) and their role in biology and the pathophysiology of various diseases has grown significantly over the past three decades, particularly following the discovery of VHL gene variants in Von Hippel–Lindau (VHL) disease, which is a hereditary tumor predisposition syndrome characterized by neuroendocrine tumors, including paraganglioma/pheochromocytoma (PPGL) 1 , 2 , 3 . Building on this foundation, we identified somatic variants in HIF2A ( EPAS1 ) in multiple individuals with a syndrome of a triad of PPGL, polycythemia, and somatostatinoma, also known as Pacak–Zhuang syndrome (PZS) 4 . Since their initial discovery in VHL disease 5 , HIFs have long been recognized as critical mediators of homeostasis and biological processes, including angiogenesis, proliferation, and migration 2 . In the presence of oxygen, HIF-α proteins are hydroxylated by prolyl-hydroxylase domain-containing proteins (PHD), then ubiquitinated by VHL complex and degraded by the proteosome 2 . In response to hypoxia, HIF-α proteins are stabilized and dimerize with HIF-ß, and the complex travels to the nucleus, binding to hypoxia response elements (HRE) across the genome, altering gene expression. The discovery of HIF2A pathogenic variants not only explained the syndromic manifestation but also established the first direct causative link between hypoxia signaling and cancer biology 4 , 6 . Since the initial findings, we have continued to investigate this syndrome, expanding our understanding of the role of HIF-2α in clinically observed neurodevelopmental and vascular anomalies. Moreover, the investigation of HIF-2α in PPGL pathophysiology catapulted efforts to molecularly stratify these tumors into three main clusters: Cluster 1—pseudohypoxia cluster— related to HIF-2α and Krebs cycle defect, Cluster 2 related to increased kinase activity, and Cluster 3 related to the Wnt signaling pathway.
TL;DRThe combination of the timing of variant acquisition and molecular pathogenicity into a schema to understand phenotypic severity in Pacak-Zhuang syndrome is proposed, with implications for other diseases. (Semantic Scholar)