PRKACA: A new gene for ACTH independent Cushing’s syndrome

Hormones

24 Aug 2016

Up to half of all people with cortisol-producing adenomas associated with Cushing’s syndrome have unique somatic mutations in the PRKACA gene, delegates have heard.

Delivering this year’s ESA TAFT lecture international expert Dr Constantine Stratakis from the NIH National Institute of Child Health and Human Development, Bethesda in the US said his work and that of colleagues over many years had now implicated the mutation in the excess secretion of the hormone cortisol.

“Today the average patient that you will see with Cushing’s syndrome with a cortisol producing adenoma has a 50% chance of having an activating mutation of the catalytic subunit – that’s remarkable,” he told delegates attending his talk on the genetics of adrenal disease.

“Clearly this mutation is involved in increasing cortisol secretion,” he said.

The PRKACA gene contains the information needed to make a subunit of the PKA (protein kinase A) enzyme, which is involved in several chemical reactions in the cell.

What was also remarkable was that its function and expression showed a dose-dependent effect, Dr Stratakis told delegates.

The more copies of the gene a person had, the more severe disease and the earlier the presentation.

“If you have one or two copies you’re normal, if you have three copies you have mild Cushing’s, if you have four copies you have a more severe form of Cushing’s,” he explained.

“There are not that many genes in the human genome that are so highly titrated where a simple addition of one allele causes disease and an addition of two alleles causing even more severe disease,” he told the audience.

“This is unusual – the human genome doesn’t work like this,” he said.

“I am not sure I understand why the catalytic subunit of Protein Kinase A is so tightly regulated…it’s unusual and it’s very interesting genetically and developmentally,” he added.

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