Functional characterization of SDHB variants: Advancing succinate dehydrogenase biology and variant curation in hereditary paraganglioma
Roderick Clifton-Bligh
Roderick Clifton-Bligh
View: Text | PDF
Commentary

Functional characterization of SDHB variants: Advancing succinate dehydrogenase biology and variant curation in hereditary paraganglioma

Abstract

Germline variants in the gene encoding succinate dehydrogenase subunit B (SDHB) occur in around 10% of all patients with pheochromocytomas and paragangliomas (PPGLs). Diagnosis of these variants has profound implications not only for the patient but also their first-degree relatives in terms of risk for PPGLs and other SDHB-associated tumors (renal cell cancer and gastrointestinal stromal tumors). Appropriate surveillance of SDHB variant carriers is associated with reduced mortality from these cancers. Curation of disease-causing (pathogenic) variants from benign variants is therefore crucial; however, this task is often difficult for missense variants when their impact on biological function is unclear. In this issue of the JCI, Lee et al. have described a newly developed cellular complementation assay for SDHB function that may assist variant curation in clinical practice and thereby improve outcomes for patients inheriting these cancer-risk variants.

Authors

Roderick Clifton-Bligh

×

Figure 1

A high throughput assay to identify SDHB variants associated with SDH loss of function and PPGL risk.

Options: View larger image (or click on image) Download as PowerPoint
A high throughput assay to identify SDHB variants associated with SDH lo...
(A) The SDH enzyme converts succinate to fumarate in the Krebs (TCA) cycle, and variants in its subunits impair its function, leading to accumulation of succinate. Succinate is considered an oncometabolite due to its accumulation’s effects on α-ketoglutarate–dependent (α-KG-dependent) dioxygenases that are associated with tumor development. Pathogenic variants in SDH subunits, including in SDHB, are associated with developing PPGLs, renal cell cancers, and gastrointestinal stromal tumors. (B) Appropriate diagnosis and surveillance of SDHB carriers enables early detection of these tumors and improved outcomes. Curation of SDHB variants as pathogenic/likely pathogenic (P/LP) or benign can be difficult, and many variants remain classified as a variant of uncertain significance (VUS). Lee et al. developed an assay using transient transfection of SDHB-variant–containing plasmids into SDHB-KO HEK293 cells, followed by measuring succinate and fumarate by LC/MS-MS. The succinate/fumarate ratio is then transformed to a metric of SDH activity, which accurately distinguishes benign (high activity) from pathogenic variants (low activity).