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Endocrine Abstracts (2014) 34 OC3.3 | DOI: 10.1530/endoabs.34.OC3.3

SFEBES2014 Oral Communications Steroids (6 abstracts)

The 21-hydroxylase pseudogene may have a role in induction of tolerance to steroidogenic machinery

Anna Louise Mitchell 1 , Ingeborg Bronstad 2 , Anette Boe Wolff 2 , Alekhya Narravula 1 , Beate Skinningsrud 3 , Eystein S Husebye 2 & Simon H S Pearce 1


1Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK; 2Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway; 3Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.


The 21-hydroxylase (21OH) gene, CYP21A2, encodes the 21OH steroidogenic enzyme which is the primary autoantigen in autoimmune Addison’s disease (AAD). It is located on chromosome 6p21, in a copy number repeat termed RCCX, adjacent to the 21OH pseudogene (CYP21A1P). CYP21A1P is highly homologous to CYP21A2 but contains an 8 bp deletion in exon 3 (707-714delGAGACTAC) which results in a frameshift. The predicted protein product is therefore truncated and not enzymatically functional. We hypothesise that CYP21A1P transcripts are expressed in human thymus to induce immune tolerance to the steroidogenic machinery, without allowing generation of glucocorticoid.

We used a PCR method to determine whether individuals with AAD from the UK and Norway are more likely to have no copies of CYP21A1P compared to controls. HLA data available for the Norwegian cohort were then analysed to determine whether CYP21A1P absence is associated with the 8.1 ancestral HLA haplotype (8.1 AH). Quantitative PCR (qPCR) was then used to determine whether CYP21A1P transcripts are detectable in thymus tissue from seven individuals (age 8 days to 16 months).

Of 315 UK AAD individuals, 55 (17.5%) had no CYP21A1P genomic DNA copies compared with 19/627 (3.0%) controls (P 8.1×10−15, OR 6.77 (95% CI 3.94–11.63)). In the Norwegian cohort, a less marked association was observed: 42/319 (13.2%) AAD compared to 19/413 (4.6%) controls (P 3.2×10−5, OR 3.14 (1.79–5.52)). HLA haplotype reconstruction showed that CYP21A1P absence is strongly associated with the 8.1 AH in both cases (P 9.6×10−7) and controls (P 1.2×10−7). qPCR demonstrated the presence of CYP21A1P transcripts at low levels in thymus tissue (mean 8 copies/μl, range 3–24).

This study has demonstrated that absence of genomic CYP21A1P is associated with AAD and is likely tagging the HLA 8.1 AH. CYP21A1P transcripts are present in thymus tissue and therefore could have a role in induction of tolerance. This exciting finding suggests a functional role for CYP21A1P and is consistent with the conservation of the pseudogene in other primates and rodents.

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