Succinate dehydrogenase variants in paraganglioma: why are B subunit variants 'bad'?

Abstract

Mutations that predispose to familial pheochromocytoma and paraganglioma include inherited variants in the four genes (SDHA, SDHB, SDHC and SDHD) encoding subunits of succinate dehydrogenase (SDH), an enzyme of the mitochondrial tricarboxylic acid cycle and complex II of the electron transport chain. In heterozygous variant carriers, somatic loss of heterozygosity is thought to result in tumorigenic accumulation of succinate and reactive oxygen species. Inexplicably, variants affecting the SDHB subunit predict worse clinical outcomes. Why? Here we consider two hypotheses. First, relative to SDH A, C and D subunits, the small SDHB subunit might be more intrinsically 'fragile' to missense mutations because of its relatively large fraction of amino acids contacting prosthetic groups and other SDH subunits. We show evidence that supports this hypothesis. Second, the natural pool of human SDHB variants might, by chance, be biased toward severe truncating variants and missense variants causing more disruptive amino acid substitutions. We tested this hypothesis by creating a database of known SDH variants and predicting their biochemical severities. Our data suggest that natural SDHB variants are more pathogenic. It is unclear if this bias is sufficient to explain clinical data. Other explanations include the possibility that SDH subcomplexes remaining after SDHB loss have unique tumorigenic gain-of-function characteristics, and/or that SDHB may have additional unknown tumor-suppressor functions.

Keywords: missense variant; paraganglioma; pathogenicity; pheochromocytoma; succinate dehydrogenase.

Figure 1

Approach to hypothesis test. (A) SDH subunit structure based on porcine complex 1ZOY in pdb. (B) Operating hypothesis.

Figure 2

Schematic illustration of SDH subunits and amino acid contacts. Mature SDH subunit size (amino acids) is indicated along with contacts with interfaces and prosthetic group (FAD, Fe-S clusters, heme) or prosthetic group insertion signals (I/LYR motifs) from Protein Contact Atlas), based on porcine complex 1ZOY in pdb.