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Uncovering the purpose of the CYP21A1P pseudogene


  • In 2015, the ADSHG's medical research grant was awarded to Dr Anna Mitchell, Academic Clinical Lecturer at the Institute of Genetic Medicine, Newcastle University. Below, she explains the study she carried out with this award. Preliminary findings from Dr Mitchell's associated stream of genetic research were presented at ENDO 2016, the annual conference of the US Endocrine Society which can be read in the abstract here.

Autoimmune Addison’s disease occurs when the immune system, which is designed primarily to fight off infection, attacks and destroys cells in the cortex of the adrenal glands. The main target of the immune system attack is the 21-hydroxylase enzyme, which is a protein that is crucial for making steroid hormones. The gene that contains the instructions needed to build the 21-hydroxylase enzyme is called CYP21A2. We know from studies into another condition (called congenital adrenal hyperplasia) that if the CYP21A2 gene is damaged or mutated, the process of manufacturing steroids is disrupted, leaving the patient dependent on steroid tablets for survival.


Sitting close to the CYP21A2 gene is another portion of DNA sequence called CYP21A1P. This sequence is known as a pseudogene because it is very similar to the sequence of the CYP21A2 gene, but unlike the gene, it contains a fault meaning that a fully functioning 21-hydroxylase enzyme cannot be made from the information contained in its sequence.


Human DNA contains many pseudogenes but they have largely been assumed to be ‘junk’, ie without a purpose. Yet, why do these pseudogenes still exist? They are conserved in human DNA and are also seen in the DNA of other animals, such as primates and rodents. When a portion of DNA is highly conserved, it makes you wonder if it has a purpose...


To study this, we have already done some work to look at whether people with autoimmune Addison’s disease have more, less, or the same number of copies of the CYP21A1P pseudogene compared to unaffected people. So far, we have found that 17.5% of people with autoimmune Addison’s disease have no copies of the CYP21A1P pseudogene compared to just 2.9% of unaffected people. We are now planning further work to determine the relevance of this finding. This involves first showing that the CYP21A1P pseudogene DNA is converted to mRNA, which is the template or pattern for protein production. Then, we need to see if the mRNA is actually converted to a protein which can be detected in human tissues.


We hope that by learning more about the genetic changes found in people with autoimmune Addison’s disease, we can move on to better understand how and why autoimmunity develops. In the longer term, we hope that this will better equip us to treat, and even perhaps prevent, this condition. I am very grateful to the ADSHG for supporting my research and I look forward to letting you know my findings in the future.


Dr Anna Mitchell









This article was first published in the September 2015 edition of the ADSHG newsletter.

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The Addison’s Disease Self-Help Group is the support group for people with Addison’s disease or adrenal insufficiency and their families in the UK and Ireland.The group was formed in 1984 and is a UK registered charity no. 1179825.

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