Creation of Armc5 Knockout Mice: First Adrenal Gland Rare Disease Model

Creation of Armc5 Knockout Mice: First Adrenal Gland Rare Disease Model

“However, after more than ten years of research, a group at the University of Montreal Hospital Research Centre (CRCHUM) have created the first rare disease animal model involving the adrenal glands.”

Cushing’s syndrome is a rare endocrine disorder involving the excess production of cortisol from the adrenal gland and affects less than 1% of the general population.1 Currently, there is no cure for this disease and treatment options only alleviates the symptoms of the condition.1 However, after more than ten years of research, a group at the University of Montreal Hospital Research Centre (CRCHUM) have created the first rare disease animal model involving the adrenal glands. The researchers reported the discovery of an unidentified disease involving the adrenal gland following the successful deletion of the Armc5 gene in experimental mice, which encodes a protein with unknown function. The disease was given the name “Armadillo syndrome” and was found to share similar symptoms to Cushing’s syndrome. Researchers hope to use this mouse model to study this rare disease and develop novel therapeutics to treat the condition.1


“This mammalian has shaped our understanding of biology and medicine over the last two decades, and have allowed scientists to study and develop treatments for human diseases such as AIDS, cardiac disease, and cancer.”

Mice are humanity’s greatest ally in medical and scientific research, with groundbreaking discoveries using mice based experimentation winning numerous Nobel prizes.2 This mammalian has shaped our understanding of biology and medicine over the last two decades, and have allowed scientists to study and develop treatments for human diseases such as AIDS, cardiac disease, and cancer.3,4 Mice have become a cornerstone of scientific discovery due to a combination of many factors such as genetic similarity to humans, economic advantages compared to other animal models, and practicality. Mouse models are 80-85% genetically alike to humans and offer a way to study diseases in the context of the complex biology of animals.4 Following the complete mapping of the mouse genome in 2002, it was subsequently compared to the human genome, allowing researchers to translate any findings using mice to the context of human biology. The modification of DNA in mice is a common practice in disease research, with over 450 strains of mice modeling a host of different genotypes and phenotypes of various disorders.4 For example, the Severe Combined Immunodeficiency (SCID) mouse strain helped identify the pathology of the SCID disorder, a disease where individuals lack a functioning immune system to defend against pathogens.5 Researchers also utilize disease mouse models to test new therapeutics to determine the efficacy and safety of the treatment before being employed in human trials. By deleting or “knocking out” genes suspected of causing a disease, one is given the means to study the pathology of the disorder. These knockout mice have been used to test new treatment options before being utilized in humans.6


“The creation of the Armc5 knockout mice hallmarks the potential beginning of new treatment options for patients suffering from Cushing’s syndrome.”

The creation of the Armc5 knockout mice hallmarks the potential beginning of new treatment options for patients suffering from Cushing’s syndrome.7 As the pathology of the disease becomes better understood through the new mouse model, new molecular targets for treatments may arise that alleviates the symptoms of the disorder with greater efficacy and safety. Researchers at CRCHUM identified 30 genes potentially related to the pathology of this rare form of Cushing’s syndrome and knocked out each gene individually to observe the impact in mice. The Armc5 knockout was found to be the most significant, with half of the mice dying during embryonic development and surviving mice being much smaller than healthy mice. Armc5 knockout mice also had weak immune systems and high levels of cortisol in their blood. Interestingly, genetic studies in patients suffering from Cushing’s syndrome revealed that 25–50% of patients affected by the disease were carriers of mutations in the Armc5 gene. This suggests that Cushing’s syndrome patients may have increased susceptibility to infections. The Armc5 gene is currently being tested as a potential biomarker for early detection and screening of this rare form of Cushing’s syndrome.7

The creation of mouse models also gives insight to previously unidentified symptoms of diseases. The knockout of Armc5 genes in mice results in bent tails, which suggests that these mice have developmental problems in their spinal cords.1 Patients with the rare form of Cushing’s syndrome may therefore also have other developmental abnormalities that have not been pronounced enough to be observed. The primary organ affected in Cushing’s syndrome, however, is the adrenal gland, and the precise role the Armc5 protein plays within this organ remains unknown. Researchers at CRCHUM hope to utilize this model to better understand this protein’s function and how mutations in the Armc5 gene may result in diseases.1

The adrenal gland is located on top of each kidney and produces hormones that play a crucial role during times of stress.8 Three different hormones are generated by this gland: 1) cortisol: facilitates the response to injury, 2) testosterone: male sex hormone that plays a role in early development, and 3) mineralocorticoids: regulates salt and water levels.8 The overproduction of cortisol results in delayed growth and excessive weight in patients with Cushing’s syndrome, which subsequently results in greater risk for cardiovascular disease due to elevated blood pressure.9 Current treatment options vary depending on the severity of the disease. There is currently no definite cure for Cushing’s disease, and in the severest cases, the adrenal glands are removed. This procedure has a significant risk of developing Nelson syndrome, a disorder characterized by dysregulation of hormone production from the pituitary gland.9 These complications highlight a need for novel treatment options for patients with Cushing’s disease and research using Armc5 knockout mice may be the key to the development of new therapeutics.

The complex range of symptoms involving the immune system and the endocrine system in the new “Armadillo syndrome” in Armc5 knockout mice signifies an unexplored area of research for Cushing’s disease.7 This finding suggests that the interplay between the immune system and the adrenal gland may be involved in disease pathology. Treatment options that help alleviate the immunological consequences of the illness in these patients may be another source of novel treatments in the future.

The development of the Armc5 knockout mice has stirred excitement in the scientific community because it signifies exciting new possibilities of treatment for patients suffering from Cushing’s syndrome in the future. This groundbreaking finding from researchers at CRCHUM highlights the significant role mice have played throughout the history of medicine. Developing new strains of our greatest ally in research may be the key to the next big discovery in rare disease treatment.


Works Cited:

1. Hu Y, Lao L, Mao J, et al. Armc5 deletion causes developmental defects and compromises T-cell immune responses. Nat Commun. 2017;8:13834. doi:10.1038/ncomms13834.

2. Nobel Prizes. Animal Research. http://www.animalresearch.info/en/medical-advances/nobel-prizes/. Published 2017.

3. Uhl EW, Warner NJ. Mouse Models as Predictors of Human Responses: Evolutionary Medicine. Curr Pathobiol Rep. 2015;3(3):219-223. doi:10.1007/s40139-015-0086-y.

4. Vandamme TF. Use of rodents as models of human diseases. J Pharm Bioallied Sci. 2014;6(1):2-9. doi:10.4103/0975-7406.124301.

5. Vladutiu AO. The severe combined immunodeficient (SCID) mouse as a model for the study of autoimmune diseases. Clin Exp Immunol. 1993;93(1):1-8. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1554753/.

6. Hall B, Limaye A, Kulkarni AB. Overview: Generation of Gene Knockout Mice. Curr Protoc Cell Biol. 2009;CHAPTER:Unit-19.1217. doi:10.1002/0471143030.cb1912s44.

7. Solt L. A NEW IMMUNOLOGIC AND ENDOCRINE SYNDROME. CRCHUM.

8. Iacobellis G, Rossi GP, Castinetti F, Letizia C. Disease of Adrenal Glands. Int J Endocrinol. 2015;2015:403521. doi:10.1155/2015/403521.

9. Rogers G. Cushing Syndrome. Health Line. http://www.healthline.com/health/cushing-syndrome?m=2. Published 2016.


Cite This Article:

Chon J., Zheng K., Chan G., Ho J. Creation of Armc5 Knockout Mice: First Adrenal Gland Rare Disease Model. Illustrated by M. Yi. Rare Disease Review. August 2017. DOI:10.13140/RG.2.2.18265.01120.

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