Abstract

Various missense mutations in the VHL gene have been reported among patients with familial bilateral pheochromocytoma. However, the p.Arg82Leu mutation in the VHL gene described here among patients with familial bilateral pheochromocytoma, has never been reported previously in a germline configuration. Interestingly, long-term follow-up of these patients indicated that the mutation might have had little impact on the normal function of the VHL gene, since all of them have remained asymptomatic. We further attempted to correlate this information with the results obtained by in silico analysis of this mutation using SIFT, PhD-SNP SVM profile, MutPred, PolyPhen2, and SNPs&GO prediction tools. To gain, new mechanistic insight into the structural effect, we mapped the mutation on to 3D structure (PDB ID 1LM8). Further, we analyzed the structural level changes in time scale level with respect to native and mutant protein complexes by using 12 ns molecular dynamics simulation method. Though these methods predict the mutation to have a pathogenic potential, it remains to be seen if these patients will eventually develop symptomatic disease.

Highlights

  • Pheochromocytomas (PCC) are rare tumors arising from the chromaffin-cells of the adrenal medulla

  • We describe the details of three members a family who presented with only bilateral pheochromocytoma, where von Hippel-Lindau (VHL) gene mutations were eventually detected when the testing system became available as part of a routine screening of patients with PCC

  • G.T) missense mutation being reported among three patients from a family with bilateral pheochromocytoma (Fig. 4)

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Summary

Introduction

Pheochromocytomas (PCC) are rare tumors arising from the chromaffin-cells of the adrenal medulla. They might arise sporadically or in association with any one of the cancer syndromes that includes von Hippel-Lindau (VHL) disease, neurofibromatosis type 1 (NF 1), multiple endocrine neoplasia type 2 (MEN 2) and mutations in any one of the mitochondrial succinate dehydrogenase complex (SDHx) genes [1], [2]. Neumann et al have shown that ,30% of unselected cases of apparently sporadic PCC carry germline mutations though the percentage may vary slightly between various studies. The presence of bilateral PCC especially among young patients increases their risk of carrying a mutation and emphasizes the need to screen such patients for all susceptibility genes associated with PCC [7]

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