A novel somatic mutation implicates ATP6V0D1 in proinsulin processing


 
 
 Prohormone convertase 1/3 (PC1/3), encoded by protein convertase subtilisin kexin type 1 (PCSK1), converts inactive prohormones into biologically active peptides. Somatic mutations of insulinomas are associated with genetic defects interfering with control of insulin secretion from pancreatic beta-cells. However, somatic mutations in proinsulinomas have not been described. Here, we report a case of a proinsulinoma, with suppressed insulin and C-peptide levels.
 
 
 
 A 70-year-old woman presented with a 20-year history of ‘blackouts’. During a 72-hour fast, blood glucose level dropped to 1.9 mmol/L with suppressed plasma insulin and C-peptide levels, but proinsulin levels were raised at 37 pmol/L (<10 pmol/L). Imaging revealed three distinct DOTATATE-avid pancreatic lesions. Laparoscopic spleen-preserving distal pancreatomy was performed. In view of discordant insulin, C-peptide and proinsulin levels, whole exome sequencing analysis was performed on the tumour. In the somatic exome of the tumour, we found mutations in PCSK expression regulators, as well as a novel truncating somatic mutation in ATP6V0D1, a subunit of the ion pump that acidifies the β-cell compartments where the PCSKs act.
 
 
 
 Appropriately suppressed insulin levels in the context of hypoglycaemia do not always indicate the absence of neuroendocrine islet cell tumour and proinsulin levels may be indicated to solidify the diagnosis. In the context of elevated proinsulin levels, low insulin and C-peptide levels might be explained by somatic mutations that likely implicate proinsulin processing within the tumour. Furthermore, we propose several mechanistic candidates including ATP6V0D1. Experimental validation using cellular approaches may in future confirm pathomechanisms involved in this rare condition.
