A Novel Somatic Mutation Implicates ATP6V0D1 in Proinsulin Processing.

Area of Science:

• Endocrinology
• Oncology
• Genetics

Background:

• Prohormone convertase 1/3 (PC1/3) processes prohormones into active peptides.
• Somatic mutations in insulinomas affect insulin secretion control.
• Somatic mutations in proinsulinomas have not been previously described.

Purpose of the Study:

• To report a case of proinsulinoma with suppressed insulin and C-peptide levels.
• To investigate the genetic basis of a rare proinsulinoma case.

Main Methods:

• A 70-year-old woman with a history of
• blackouts
• presented with hypoglycemia.
• Whole exome sequencing was performed on tumor samples.
• Analysis of discordant insulin, C-peptide, and proinsulin levels.

Main Results:

• The patient exhibited hypoglycemia with suppressed insulin and C-peptide but elevated proinsulin levels.
• Three distinct DOTATATE-avid pancreatic lesions were identified.
• Novel truncating somatic mutation in ATP6V0D1 and PCSK expression regulator mutations were found in the tumor exome.

Conclusions:

• Elevated proinsulin levels can indicate neuroendocrine islet cell tumors, even with suppressed insulin.
• Somatic mutations, such as in ATP6V0D1, may explain impaired proinsulin processing in proinsulinomas.
• Further research with cellular models is needed to confirm the pathomechanisms of this rare condition.