Germline Mutations in the Mitochondrial 2-Oxoglutarate/Malate Carrier SLC25A11 Gene Confer a Predisposition to Metastatic Paragangliomas

Comprehensive genetic analyses have identified germline and gene mutations as predominant causes of metastatic paraganglioma and pheochromocytoma. However, some suspicious cases remain unexplained. In this study, we performed whole-exome sequencing of a paraganglioma exhibiting an -like molecular profile in the absence of or mutations and identified a germline mutation in the gene, which encodes the mitochondrial 2-oxoglutarate/malate carrier. Germline mutations were identified in six other patients, five of whom had metastatic disease. These mutations were associated with loss of heterozygosity, suggesting that acts as a tumor-suppressor gene. Pseudohypoxic and hypermethylator phenotypes comparable with those described in - and -related tumors were observed both in tumors with mutated and in immortalized mouse chromaffin knockout cells generated by CRISPR-Cas9 technology. These data show that is a novel paraganglioma susceptibility gene for which loss of function correlates with metastatic presentation. A gene encoding a mitochondrial carrier is implicated in a hereditary cancer predisposition syndrome, expanding the role of mitochondrial dysfunction in paraganglioma. .