Recurrent somatic mutations underlie corticotropin-independent Cushing’s syndrome
Copyright policy )Recurrent somatic mutations underlie corticotropin-independent Cushing’s syndrome
Cushing’s syndrome is caused by excess cortisol production from the adrenocortical gland. In corticotropin-independent Cushing’s syndrome, the excess cortisol production is primarily attributed to an adrenocortical adenoma, in which the underlying molecular pathogenesis has been poorly understood. We report a hotspot mutation (L206R) in PRKACA , which encodes the catalytic subunit of cyclic adenosine monophosphate (cAMP)–dependent protein kinase (PKA), in more than 50% of cases with adrenocortical adenomas associated with corticotropin-independent Cushing’s syndrome. The L206R PRKACA mutant abolished its binding to the regulatory subunit of PKA (PRKAR1A) that inhibits catalytic activity of PRKACA, leading to constitutive, cAMP-independent PKA activation. These results highlight the major role of cAMP-independent activation of cAMP/PKA signaling by somatic mutations in corticotropin-independent Cushing’s syndrome, providing insights into the diagnosis and therapeutics of this syndrome.
- Kyoto University Japan
- University of Tokyo Japan
Cyclic AMP-Dependent Protein Kinase Catalytic Subunits, DNA Mutational Analysis, PC12 Cells, Adrenal Cortex Neoplasms, GTP-Binding Protein alpha Subunits, Rats, Mice, HEK293 Cells, Adrenocorticotropic Hormone, Catalytic Domain, Adrenocortical Adenoma, Mutation, NIH 3T3 Cells, Animals, Humans, Cushing Syndrome
Cyclic AMP-Dependent Protein Kinase Catalytic Subunits, DNA Mutational Analysis, PC12 Cells, Adrenal Cortex Neoplasms, GTP-Binding Protein alpha Subunits, Rats, Mice, HEK293 Cells, Adrenocorticotropic Hormone, Catalytic Domain, Adrenocortical Adenoma, Mutation, NIH 3T3 Cells, Animals, Humans, Cushing Syndrome
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