Somatic GNAQ, CTNNB1, and CACNA1C Mutations in Cat Aldosterone-Secreting Tumors

Watson, A; Syme, H; Brown, M

Abstract

BACKGROUND:Primary aldosteronism (PA) is a common cause of human hypertension. Somatic mutations in KCNJ5, CACNA1D, ATP1A1, and ATP2B3 are found in at least 80% of aldosterone-producing adenomas, which cause unilateral PA in humans. Somatic mutations have been identified infrequently in 7 other genes; few of these were known to play a role in aldosterone secretion before the discovery of their mutations. Interrogating somatic mutations in the domestic cat, in which spontaneous PA is also known to occur, might improve the understanding of normal adrenal gland physiology and the pathophysiology of PA.METHODS:DNA and RNA extracted from tissue from 13 cats with unilateral aldosterone-secreting tumors, including 8 carcinomas and 5 adenomas, underwent whole genome sequencing, targeted Sanger sequencing, and RNA sequencing. Single-nucleotide substitution variants were filtered to select those with a predicted deleterious effect on protein function and a suspected role in aldosterone secretion.RESULTS:Probable functional somatic single-nucleotide polymorphisms (n=8) were found in 3 adenomas and 2 carcinomas. Mutations with predicted significant effects were identified in 2 genes also mutated in human PA; GNAQ and CTNNB1, and in a residue of CACNA1C analogous to a common CACNA1D mutation. In contrast to humans, CACNA1C expression was much greater than CACNA1D in both feline tumor and nontumor adrenal tissue. No mutations were identified in KCNJ5, CACNA1D, ATP1A1, or ATP2B3.CONCLUSIONS:Similar mutations were identified in cats to those found in humans. It is, therefore, likely that both species have shared underlying selection pressures for mutations that increase aldosterone secretion.

Citation

Watson, A., Syme, H., & Brown, M. (2024). Somatic GNAQ, CTNNB1, and CACNA1C Mutations in Cat Aldosterone-Secreting Tumors. Hypertension, 81(12), 2489-2500. https://doi.org/10.1161/HYPERTENSIONAHA.124.23501

• Journal Article Type: Article
• Acceptance Date: Oct 4, 2024
• Online Publication Date: Oct 21, 2024
• Publication Date: 2024
• Deposit Date: Dec 3, 2024
• Publicly Available Date: Dec 3, 2024
• Journal: Hypertension
• Print ISSN: 2224-1485
• Electronic ISSN: 2307-1095
• Publisher: Publishing House Zaslavsky
• Peer Reviewed: Peer Reviewed
• Volume: 81
• Issue: 12
• Pages: 2489-2500
• DOI: https://doi.org/10.1161/HYPERTENSIONAHA.124.23501
• Keywords: aldosterone; animals; hyperaldosteronism; hypertension; mutation; PRIMARY HYPERALDOSTERONISM; CHANNEL MUTATIONS; ADENOMAS; HYPERTENSION; AMLODIPINE; EXPRESSION; MANAGEMENT; ALIGNMENT; SOCIETY; ATP1A1