New study identifies the main genetic causes of autoimmune Addison’s disease

Novel genetic associations could pave the way for early interventions and personalized treatment of an incurable condition.

Scientists from the University of Bergen (Norway) and Karolinska Institutet (Sweden) have discovered the genes involved in autoimmune Addison’s disease, a condition where the body’s immune systems destroys the adrenal cortex leading to a life-threatening hormonal deficiency of cortisol and aldosterone.

Groundbreaking study

The rarity of Addison’s disease has until now made scanning of the whole genome for clues to the disease’s genetic origins difficult, as this method normally requires many thousands of study participants. However, by combining the world’s two largest Addison’s disease registries, Prof. Eystein Husebye and his team at the University of Bergen and collaborators at Karolinska Institutet in Sweden (prof. Kämpe) were able to identify strong genetic signals associated with the disease. Most of them are directly involved in the development and functioning of the human immune system including specific molecular types in the so-called HLA-region (this is what makes matching donors and recipients in organ transplants necessary) and two different types of a gene called AIRE (which stands for AutoImmune REgulator).

AIRE is a key factor in shaping the immune system by removing self-reacting immune cells. Variants of AIRE, such as the ones identified in this study, could compromise this elimination of self-reacting cells, which could lead to an autoimmune attack later in life.

Knowing what predisposes people to develop Addison’s disease opens up the possibilities of determining the molecular repercussions of the predisposing genetic variation (currently ongoing in Prof. Husebye’s lab). The fact that it is now feasible to map the genetic risk profile of an individual also means that personalised treatment aimed at stopping and even reversing the autoimmune adrenal destruction can become a feasible option in the future.


Contact information:

Professor at the University of Bergen, Eystein Husebye – – cell phone +47 99 40 47 88

Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.


Tumors in Cushing’s Patients Have Distinct Genetic Profiles

A study examining the genes expressed in pituitary tumors of Cushing’s disease patients found that these tumors may be grouped into three distinct subsets.

The finding suggests that different biological processes contribute to the development of each subset, an insight that may aid in developing targeted therapies.

The study, “Gene expression profiling in human corticotrope tumors reveals distinct, neuroendocrine profiles,” was published in the Journal of Neuroendocrinology.

In Cushing disease, a pituitary tumor producing excess amounts of the adenocorticotropic hormone causes the body to produce too much cortisol.

Pituitary tumors respond differently to modulators of ACTH secretion, and patients have different disease manifestations, but what makes them differ from one another is unknown.

To determine if the genetic profile of tumors could explain the clinical diversity reported in these patients, Italian researchers evaluated 40 benign, ACTH-secreting pituitary tumors removed from patients with Cushing’s disease.

Of the 20,815 genes examined in the study, 1,259 were significantly elevated in the pituitary tumors. These were mostly involved in pathways that kept the neuroendocrine cell profile.

Based on their genetic profile, researchers were able to cluster tumors into three distinct subgroups. Samples in group A had four specific genes, associated with tumor-related processes, that were overly active. In group B, there were 313 overly active genes, involved in many of the mechanisms of hormone-secreting adenomas.

Group C had 29 highly active genes, all involved in calcium influx and cell growth – mechanisms that are important for the development of ACTH-secreting adenomas.

“It appears that these tumors present a neuroendocrine cell profile but, at the same time, clearly distinct gene expression patterns [are seen] in individual subgroups,” the researchers wrote.

Looking at clinical characteristics that correlated with each subgroup, the researchers found that most group A patients  had macroadenomas (large tumors) that had invaded the sella – the compartment where the pituitary gland resides at the base of the brain. These patients were also older than those in the other two subgroups.

Some patients in group B also had macroadenomas, but no such tumors were seen in group C. However, researchers found no association between the groups and the hormonal values, clinical findings, or surgical outcomes.

Collectively, the findings add new clues to the molecular mechanisms involved in the progression of benign pituitary tumors. They also provide new ground for developing targeted therapies, the researchers said.


Cushing’s disease associated with USP8 mutations



April 04, 2016

Oral Session: Pituitary Patients and Outcomes

Cushing’s disease associated with USP8 mutations

RR Correa, FR Faucz, A Angelousi, N Settas, P Chittiboina, MB Lodish, CA Stratakis

Summary: In Cushing’s disease (CD), pituitary corticotroph adenomas secrete excessive adrenocorticotropic hormone (ACTH), resulting in hypercortisolism. Often, the genetic pathogenesis of CD remains unknown, but recent studies have shown that the ubiquitin-specific protease 8 gene (USP8) is frequently mutated in CD. This gene codes for a protein deubiquitinase that inhibits the lysosomal degradation of the epidermal growth factor receptor. Researchers determined that pediatric patients with USP8 mutations were predominantly female and presented with higher ACTH levels than control patients.


  • To further study the prevalence of mutations in USP8, researchers sequenced the complete USP8-coding and surrounding intronic regions in 97 patients with diagnosed CD by Sanger sequencing of germline DNA (n=97) and tumor DNA (n=50).
  • They analuzed biochemical and clinical characteristics in all the patients with predicted (by in silico analysis) damaging USP8 mutations and it was compared to patients without the mutation (control).


  • Overall researchers identified 18 (18.5%) patients with corticotroph adenomas who had USP8mutations, 13 with germline mutation, 2 with a germline and a new somatic mutation, and 5 with somatic mutation only.
  • All the somatic mutations that were not present at the germline level were mutations in the previously described hotspot.
  • Female-to-male ratio in the patients with USP8 mutations was 3.5:1 compared to the control ratio of 1:1 (P=0.05).
  • The mean age was 13 years old (range 6-18) and 72% (13/18) were whites.
  • Three of the mutant tumors were macroadenomas (≥ 1 cm) and 15 were microadenomas (< 1 cm).
  • In cases, mean basal plasma ACTH was 53.2±28.5 pg/mL and 39.6±19.1 pg/mL in the control group (P=0.02).
  • Researchers did not note any statistically significant differences in cortisol levels between the groups.

What Genes are Related to Cushing’s Disease?



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.


Webinar: How to Discuss Genetic Disease with Your Loved Ones

Date:  April 1, 2015
Time:  11:00 am PT / 2:00 pm ET

register button

There are currently about 7,000 rare diseases identified worldwide, and approximately 80 percent of these are caused by genetic changes. But genetics is a topic that not all of us are familiar with.

This webinar covers the basics of the underlying genetics of rare disease and provides viewers with the strategies and advice to discuss them with the ones they love.

Panelists will share strategies they have used to explain genetic disease, challenges they faced, and helpful resources.

jenna_recombine Jenna Miller, MS, CGC, Genetic Counselor, Recombine

Jenna Miller is a certified genetic counselor at Recombine, a genetic testing company based in New York, NY. She works closely with families seeking preconception and prenatal genetic carrier screening and noninvasive prenatal screening. She also assists physicians and genetic counselors to facilitate appropriate genetic testing procedures. Jenna is passionate about genetics education; her Master’s thesis project involved developing and teaching a Genetics 101 class for student inmates at a maximum security women’s prison. Jenna is an advocate for informed consent, ethical approaches to genetic testing, and support of families affected by genetic conditions.

cyndiCynthia Frank, Director, Patient Advocacy & Meetings, Nat’l Gaucher Foundation

Cyndi is a long-standing member of the Gaucher community and has participated in many clinical trials to help get treatments to market.  She is an NGF Mentor and advocate for Gaucher patients and raising awareness through speaking at conferences, meetings and events, including NGF and other rare and genetic disease-organization meetings, LSD symposiums, and industry and pharmaceutical conferences and educational events.  She serves on multiple boards and committees for many organizations, including the Global Genes Advocacy Leaders Group and the NGF’s Gaucher Advisory Group.

jmillsJanet Mills, Trustee and Patient Advocate, cureCADASIL Association

Janet is often the first point of contact when a new patient is diagnosed with the rare genetic disease CADASIL. She serves on the Board of Trustees of cureCADASIL, and she networks with others in the rare disease community online and at  events. She recently spoke about the genetics behind CADASIL on a Los Angeles radio show. Janet has provided content for two RARE Toolkits, is a guest blogger for the RARE Daily, and has participated in the Global Genes Advocacy Advisors Group.

MichelleFoxMichelle Fox, MS, LCGC, Genetic Counselor Consultant, Invitae

For over 30 years, Michelle coordinated the UCLA Genetics Clinic, providing genetic counseling services to both pediatric and adult populations, including the UCLA Predictive Huntington Disease Testing Program, early onset Alzheimer, and genetic neurodegenerative disorders. Her expertise is both on the provision of clinical services and clinical genetic research in the areas of newborn screening, carrier screening, diagnostic testing, and predictive testing.

A focus of Michelle’s work has been on the ethical issues surrounding the provision of genetic services, shared decision making in offering genetic testing, and best practices in communicating genetic information. Educating the public and providers about genetic testing is the mission of Michelle’s professional career. Michelle is currently providing consultation services to organizations, laboratories, and businesses including Invitae.

Danny_LevineDaniel Levine, Founder & Principal, Levine Media Group

Daniel Levine is an award-winning business journalist who has reported on the life sciences, economic development, and business policy issues throughout his 25-year career. Since 2011, he has served as the lead editor and writer of Burrill Media’s acclaimed annual book on the biotech industry and hosts The Burrill Report’s weekly podcast. His work has appeared in The New York Times, The Industry Standard,, and other national publications.

%d bloggers like this: