Deficiency in PHD2-mediated hydroxylation of HIF2α underlies Pacak-Zhuang syndrome.

ABSTRACT: Pacak-Zhuang syndrome is caused by mutations in the EPAS1 gene, which encodes for one of the three hypoxia-inducible factor alpha (HIFα) paralogs HIF2α and is associated with defined but varied phenotypic presentations including neuroendocrine tumors and polycythemia. However, the mechanisms underlying the complex genotype-phenotype correlations remain incompletely understood. Here, we devised a quantitative method for determining the dissociation constant (K_d) of the HIF2α peptides containing disease-associated mutations and the catalytic domain of prolyl-hydroxylase (PHD2) using microscale thermophoresis (MST) and showed that neuroendocrine-associated Class 1 HIF2α mutants have distinctly higher K_d than the exclusively polycythemia-associated Class 2 HIF2α mutants.

SUBMITTER: Ferens FG 

PROVIDER: S-EPMC10902354 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature