Constitutional variants and tumor-specific down-regulation of the calcium voltage-gated channel subunit CACNA1H in pheochromocytoma

ABSTRACT: Pheochromocytoma (PCC) and abdominal paraganglioma (aPGL) (together abbreviated PPGL) frequently present with an underlying genetic event in a PPGL driver gene, and additional susceptibility genes are anticipated. Here we re-analysed whole-exome sequencing data for PCC patients, and identified two patients with very rare missense variants in the calcium voltage-gated channel subunit 1H gene (CACNA1H). CACNA1H variants were also found in the clinical setting in PCC patients using targeted sequencing and analysis of The Cancer Genome Atlas database. In total, CACNA1H variants were found in 7 PCC cases. Four of these were constitutional and two are known to have functional consequences on hormone production and gene expression in primary aldosteronism and aldosterone-producing adrenocortical adenoma. In general, PPGL exhibited reduced CACNA1H mRNA expression as compared to normal adrenal. Immunohistochemistry showed strong CACNA1H (CaV3.2) staining in adrenal medulla while PPGL typically had weak staining or were negative. Furthermore, reduced CACNA1H gene expression was especially pronounced in PCC as compared to aPGL, in cases with normal norepinephrine levels and in PPGL with Cluster 2 kinase signalling phenotype. Moreover, TCGA data revealed a correlation between CACNA1H methylation density and gene expression. Expression of rCacna1h in PC12 cells induced differential protein expression profiles determined by mass spectrometry as well as a shift in the membrane potential where maximum calcium currents were observed as determined by electrophysiology. The findings add a possible novel genetic event to the growing palette of PPGL susceptibility genes and establish a potential link between the aetiology of adrenomedullary and adrenocortical tumor development.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Rattus Norvegicus (rat)

TISSUE(S): Cell Culture, Fibroblast

DISEASE(S): Pheochromocytoma

SUBMITTER: Akos Vegvari  

LAB HEAD: Akos Vegvari

PROVIDER: PXD040446 | Pride | 2024-10-17

REPOSITORIES: Pride