Mitochondrial dysfunction, due to mutations of the gene encoding succinate dehydrogenase (SDH), has been implicated in the development of adrenal phaeochromocytomas, sympathetic and parasympathetic paragangliomas, renal cell carcinomas, gastrointestinal stromal tumours and more recently pituitary tumours. Underlying mechanisms behind germline SDH subunit B (SDHB) mutations and their associated risk of disease are not clear. To investigate genotype-phenotype correlation of SDH subunit B (SDHB) variants, a homology model for human SDH was developed from a crystallographic structure. SDHB mutations were mapped, and biochemical effects of these mutations were predicted in silico. Results of structural modelling indicated that many mutations within SDHB are predicted to cause either failure of functional SDHB expression (p.Arg27*, p.Arg90*, c.88delC and c.311delAinsGG), or disruption of the electron path (p.Cys101Tyr, p.Pro197Arg and p.Arg242His). GFP-tagged WT SDHB and mutant SDHB constructs were transfected (HEK293) to determine biological outcomes of these mutants in vitro. According to in silico predictions, specific SDHB mutations resulted in impaired mitochondrial localisation and/or SDH enzymatic activity. These results indicated strong genotype-functional correlation for SDHB variants. This study reveals new insights into the effects of SDHB mutations and the power of structural modelling in predicting biological consequences. We predict that our functional assessment of SDHB mutations will serve to better define specific consequences for SDH activity as well as to provide a much needed assay to distinguish pathogenic mutations from benign variants.

plexus was 97 Gy (range,. At a median follow-up of 9 months (range, 1-47 months), the cumulative incidence of brachial plexopathy (CIBPP) was 17% at 1 year. This consisted of two cases with pain alone, one case with numbness alone, two cases with weakness alone and one case with combination of pain and numbness. The median time to development of symptoms was 8.2 months (range, 1-15 months). Among patients with a Dmax greater than vs less than 106 Gy, the 1-year cumulative incidence of BPP was 42% vs 4% P = 0.005. V80 > 1cc (1-yr CIBPP 34% vs 4% P = 0.03) and V90 > 0.3cc (32% vs 4%, P = 0.046) associated with increased risk of BPP. The use of concurrent cisplatin during re-irradiation was associated with increased risk of BPP (OR 39 CI 4.263-356.81, P = 0.001). Other variables like gender, history of neck surgery, use of other kind of systemic therapy, use of cisplatin during the first course of RT, mean cumulative dose, V60, V70, V100 and the interval between the first and the second courses of radiation were not associated with increased risk of BPP. The 1-year OS was 78% and the 1-year PFS was 52%. Conclusion: Cumulative incidence of radiation-induced BPP after re-irradiation was 17% at 1 year. Dmax > 106 Gy, higher V80/V90, and the use of concurrent cisplatin during re-irradiation, were associated with increased risk of BPP.