Somatic Mutations in MCOLN3 in Aldosterone-Producing Adenomas cause Primary Aldosteronism

Area of Science:

• Endocrinology
• Genetics
• Molecular Biology

Background:

• Primary aldosteronism is a common endocrine disorder causing hypertension, driven by excess aldosterone production from adrenal lesions.
• Somatic mutations in ion transporters/channels/pumps disrupt intracellular calcium, increasing aldosterone synthase (CYP11B2) expression and aldosterone biosynthesis.
• Many aldosterone-producing adenomas (APAs) harbor known mutations, but some lack identified genetic drivers.

Purpose of the Study:

• To investigate genetic causes of primary aldosteronism in APAs without previously identified mutations.
• To identify novel genes and mutations involved in renin-independent hyperaldosteronism.
• To elucidate the functional impact of identified mutations on aldosterone production.

Main Methods:

• Genomic analysis of APAs lacking known somatic mutations.
• Identification and characterization of mutations in the MCOLN3 gene, encoding mucolipin-3 (TRPML3).
• Functional studies using transfected adrenocortical cells to assess the impact of MCOLN3 mutations on calcium influx and CYP11B2 transcription.

Main Results:

• Novel somatic mutations (p.Y391D and p.N411_V412delinsI) in MCOLN3 were identified in three APAs from male patients.
• These mutations are located near the TRPML3 ion pore and selectivity filter.
• Functional studies demonstrated that MCOLN3 mutations increase cytosolic calcium in adrenocortical cells, leading to elevated CYP11B2 transcription and aldosterone production.

Conclusions:

• This study reports the first disease-causing MCOLN3 mutations in humans, implicating TRPML3 in primary aldosteronism.
• Mutated MCOLN3 contributes to aldosterone excess by altering calcium homeostasis and upregulating CYP11B2 expression.
• MCOLN3 mutations represent a novel genetic mechanism driving aldosterone production in primary aldosteronism.