Identified: the gene behind an unusual form of Cushing’s Syndrome

Posted on October 23, 2021 by MaryO

A team of scientists in Montreal and Paris has succeeded in identifying the gene responsible for the development of a food-dependent form of Cushing’s Syndrome, a rare disease affecting both adrenal glands.

In their study published in The Lancet Diabetes & Endocrinology, Dr. Isabelle Bourdeau and Dr. Peter Kamenicky identify in the gene KDM1A the mutations responsible for the development of this unusual form of the disease.

The scientists also show, for the first time, that the disease is genetically transmitted.

Bourdeau is a researcher and a Université de Montréal medical professor practising at the CHUM Research Centre (CRCHUM), while Kamenicky works at the Hôpital de Bicêtre, part of the Assistance publique-hôpitaux de Paris network in France.

Cushing’s Syndrome is caused by the overproduction of cortisol, a steroid hormone, by the two adrenal glands located above the kidneys.

“When the tissues of the human body are exposed to this excess of cortisol, the effects for those with the disease are serious: weight gain, high blood pressure, depression, osteoporosis, and heart complications, for example,” said Bourdeau, co-lead author of the study with Dr. Fanny Chasseloup, a colleague from the French team.

This discovery comes nearly 30 years after food-induced Cushing’s Syndrome was first described in 1992 by a research group led by Dr. André Lacroix at the CRCHUM and his colleagues Drs. Johanne Tremblay and Pavel Hamet.

The form of the disease being studied by Bourdeau and her colleagues is caused specifically by the abnormal expression of the receptors of a hormone named GIP (glucose-dependent insulinotropic peptide), in both adrenal glands of patients. This hormone is produced by the small intestine in response to food intake. For people with the disease, cortisol concentrations increase abnormally every time they ingest food.

The discovery of the genetic mechanism by the French and Quebec teams was made possible through the use of recent cutting-edge genetic techniques on tissues of patients including those investigated by Dr Lacroix at CHUM. Bourdeau was aided by CRCHUM researcher Martine Tétreault during the computer analyses related to the research project.

Earlier diagnosis thanks to genetic analysis

“In general, rare diseases are generally underdiagnosed in clinics,” said Bourdeau, the medical director of the adrenal tumors multidisciplinary team at the CHUM.

“By identifying this new gene, we now have a way of diagnosing our patients and their families earlier and thus offer more personalized medicine. At the CHUM, genetic analysis is already offered in our Genetic Medicine Division.”

In a remarkable demonstration of scientific cooperation, the Quebec and French teams were able to collect and study tissue specimens available in local and international biobanks in Canada, France, Italy, Greece, Belgium and the Netherlands.

Blood and adrenal gland tissue samples of 17 patients—mostly women—diagnosed with GIP-dependent Cushing’s Syndrome were compared genetically with those of 29 others with non-GIP-dependent bilateral adrenal Cushing’s Syndrome.

This was quite an accomplishment, given the rarity of the disease in the general population. It allowed the researchers to identify the genetic mutations of the KDM1A gene and to determine that the disease is genetically transmitted.

Since 2009, the CHUM has been designated as the adrenal tumors quaternary care centre of the Quebec Cancer Program.

About this study

“Loss of KDM1A in GIP-dependent primary bilateral macronodular adrenal hyperplasia with Cushing’s syndrome: a multicenter retrospective cohort study,” by Drs. Fanny Chasseloup, Isabelle Bourdeau and their colleagues, was published Oct. 13, 2021, in The Lancet Diabetes & Endocrinology. Funding was provided by the Agence nationale de la recherche, the Fondation du Grand défi Pierre Lavoie, the Institut national du cancer, the Fonds de recherche du Québec-Santé, INSERM and Assistance publique-hôpitaux de Paris.

About the CRCHUM

The University of Montreal Hospital Research Centre (CRCHUM) is one of North America’s leading hospital research centres. It strives to improve adult health through a research continuum covering such disciplines as the fundamental sciences, clinical research and public health. Over 1,850 people work at the CRCHUM, including more than 550 researchers and more than 460 graduate students

Media contact

  • Jeff HeinrichUniversité de MontréalTel: 514 343-7593
  • Lucie DufresneCentre hospitalier de l’Université de MontréalTel: 514 890-8000 p. 15380

From https://nouvelles.umontreal.ca/en/article/2021/10/15/identified-the-gene-behind-an-unusual-form-of-cushing-s-syndrome/

Filed under: Addison's disease, adrenal, Cushing's, Rare Diseases | Tagged: , , , | Leave a comment »

What Genes are Related to Cushing’s Disease?

Posted on July 29, 2015 by MaryO

genetic

 

The genetic cause of Cushing disease is often unknown. In only a few instances, mutations in certain genes have been found to lead to Cushing disease. These genetic changes are called somatic mutations. They are acquired during a person’s lifetime and are present only in certain cells. The genes involved often play a role in regulating the activity of hormones.

Cushing disease is caused by an increase in the hormone cortisol, which helps maintain blood sugar levels, protects the body from stress, and stops (suppresses) inflammation. Cortisol is produced by the adrenal glands, which are small glands located at the top of each kidney. The production of cortisol is triggered by the release of a hormone called adrenocorticotropic hormone (ACTH) from the pituitary gland, located at the base of the brain. The adrenal and pituitary glands are part of the hormone-producing (endocrine) system in the body that regulates development, metabolism, mood, and many other processes.

Cushing disease occurs when a noncancerous (benign) tumor called an adenoma forms in the pituitary gland, causing excessive release of ACTH and, subsequently, elevated production of cortisol. Prolonged exposure to increased cortisol levels results in the signs and symptoms of Cushing disease: changes to the amount and distribution of body fat, decreased muscle mass leading to weakness and reduced stamina, thinning skin causing stretch marks and easy bruising, thinning of the bones resulting in osteoporosis, increased blood pressure, impaired regulation of blood sugar leading to diabetes, a weakened immune system, neurological problems, irregular menstruation in women, and slow growth in children. The overactive adrenal glands that produce cortisol may also produce increased amounts of male sex hormones (androgens), leading to hirsutism in females. The effect of the excess androgens on males is unclear.

Most often, Cushing disease occurs alone, but rarely, it appears as a symptom of genetic syndromes that have pituitary adenomas as a feature, such as multiple endocrine neoplasia type 1 (MEN1) or familial isolated pituitary adenoma (FIPA).

Cushing disease is a subset of a larger condition called Cushing syndrome, which results when cortisol levels are increased by one of a number of possible causes. Sometimes adenomas that occur in organs or tissues other than the pituitary gland, such as adrenal gland adenomas, can also increase cortisol production, causing Cushing syndrome. Certain prescription drugs can result in an increase in cortisol production and lead to Cushing syndrome. Sometimes prolonged periods of stress or depression can cause an increase in cortisol levels; when this occurs, the condition is known as pseudo-Cushing syndrome. Not accounting for increases in cortisol due to prescription drugs, pituitary adenomas cause the vast majority of Cushing syndrome in adults and children.

Read more about familial isolated pituitary adenoma.

 

How do people inherit Cushing disease?

Most cases of Cushing disease are sporadic, which means they occur in people with no history of the disorder in their family. Rarely, the condition has been reported to run in families; however, it does not have a clear pattern of inheritance.

The various syndromes that have Cushing disease as a feature can have different inheritance patterns. Most of these disorders are inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder.

From http://ghr.nlm.nih.gov/condition/cushing-disease

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Genetic mutation lowers obesity in Cushing’s syndrome

Posted on January 8, 2014 by MaryO

London E. J Clin Endocrinol Metab. 2013; doi:10.1210/jc.2013-1956.

Among adult patients with Cushing’s syndrome, those with mutations in PRKAR1A, the gene that controls cAMP-dependent protein kinase, are less obese than their counterparts without these mutations, according to a recent study.

The retrospective study evaluated adrenalectomy samples from 51 patients with Cushing’s syndrome, 13 with PRKAR1A mutations and 32 without. Of the 51 patients, 40 were female and 11 were male, and patients ranged in age from 4 to 74 years.

A non-Cushing’s syndrome comparison group consisting of 6 adrenalectomy patients with aldosterone producing adenomas (APAs) was included. Additional comparison groups comprising clinical data from 89 patients with Cushing’s disease and 26 with hyperaldosteronism were also studied.

Researchers recorded the weight, height and BMI of all patients, and measured abdominal subcutaneous adipose tissue (ScAT) and periadrenal adipose tissue (PAT) using computed tomography. PAT was collected and frozen for evaluation; the extracts were assessed for levels of cAMP and protein kinase (PKA) activity, as well as for protein and mRNA expression of subunits of PKA. Diurnal cortisol levels and urine-free cortisol were also measured preoperatively.

The study found that in adults with Cushing’s syndrome, the mean BMI of those with PRKAR1A mutations was lower than that of patients with noPRKAR1A mutations (P<.05), and was not inconsistent with the hyperaldosteronism comparison group.

In pediatric patients with adrenal Cushing’s syndrome, the presence of PRKAR1A mutation did not have an impact on mean BMI z-scores. However, in comparison with pediatric patients with pituitary Cushing’s disease, the BMI z-scores were significantly lower in pediatric Cushing’s disease patients with PRKAR1Amutations (P<.05). Patients with Cushing’s syndrome without PRKAR1A mutations had significantly more PAT and ScAT than non-Cushing’s syndrome patients. Additionally, the ratio of basal-to-total (cAMP-triggered) PKA activity was significantly lower in patients with PRKAR1A mutations, suggesting greater proportions of active PKA (P<.005).

“These findings have obvious implications in the establishment of the diagnosis of CS in patients with PRKAR1A mutations: These patients may be leaner than other patients with [Cushing’s syndrome],” the study authors wrote. “Perhaps more importantly, our findings point to the importance of cAMP and or PKA signaling in the regulation of adiposity.”

Disclosures: The researchers report no relevant financial disclosures.

From http://www.healio.com/endocrinology/adrenal/news/online/%7B693f94cd-359d-4c52-8e0d-bfd0e4a51d03%7D/genetic-mutation-lowers-obesity-in-cushings-syndrome

Filed under: adrenal, Cushing's, pituitary, Rare Diseases | Tagged: , , , , , , , , , , , , , , , , , , , , , | Leave a comment »

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