Bibliographic Details
| Title: |
A deep intronic splice–altering AIRE variant causes APECED syndrome through antisense oligonucleotide-targetable pseudoexon inclusion. |
| Authors: |
Ochoa, Sebastian, Hsu, Amy P., Oler, Andrew J., Kumar, Dhaneshwar, Chauss, Daniel, van Hamburg, Jan Piet, van Laar, Gustaaf G., Oikonomou, Vasileios, Ganesan, Sundar, Ferré, Elise M. N., Schmitt, Monica M., DiMaggio, Tom, Barber, Princess, Constantine, Gregory M., Rosen, Lindsey B., Auwaerter, Paul G., Gandhi, Bhumika, Miller, Jennifer L., Eisenberg, Rachel, Rubinstein, Arye |
| Source: |
Science Translational Medicine; 9/18/2024, Vol. 16 Issue 765, p1-16, 16p |
| Subject Terms: |
LYMPHOBLASTOID cell lines, WHOLE genome sequencing, AUTOIMMUNE diseases, PROTEIN models, EPITHELIAL cells |
| Abstract: |
Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a life-threatening monogenic autoimmune disorder primarily caused by biallelic deleterious variants in the autoimmune regulator (AIRE) gene. We prospectively evaluated 104 patients with clinically diagnosed APECED syndrome and identified 17 patients (16%) from 14 kindreds lacking biallelic AIRE variants in exons or flanking intronic regions; 15 had Puerto Rican ancestry. Through whole-genome sequencing, we identified a deep intronic AIRE variant (c.1504-818 G>A) cosegregating with the disease in all 17 patients. We developed a culture system of AIRE-expressing primary patient monocyte-derived dendric cells and demonstrated that c.1504-818 G>A creates a cryptic splice site and activates inclusion of a 109–base pair frame-shifting pseudoexon. We also found low-level AIRE expression in patient-derived lymphoblastoid cell lines (LCLs) and confirmed pseudoexon inclusion in independent extrathymic AIRE–expressing cell lines. Through protein modeling and transcriptomic analyses of AIRE-transfected human embryonic kidney 293 and thymic epithelial cell 4D6 cells, we showed that this variant alters the carboxyl terminus of the AIRE protein, abrogating its function. Last, we developed an antisense oligonucleotide (ASO) that reversed pseudoexon inclusion and restored the normal AIRE transcript sequence in LCLs. Thus, our findings revealed c.1504-818 G>A as a founder APECED-causing AIRE variant in the Puerto Rican population and uncovered pseudoexon inclusion as an ASO-reversible genetic mechanism underlying APECED. Editor's summary: Biallelic mutations in the autoimmune regulator (AIRE) gene cause the autoimmune syndrome APECED (autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy). Here, Ochoa and colleagues studied 17 patients, predominantly of Puerto Rican ancestry, who were clinically diagnosed with APECED but who lacked biallelic variants in AIRE exons or flanking intronic regions. They identified a deep intronic variant in AIRE that created a cryptic splice site, leading to inclusion of a frame-shifting pseudoexon that resulted in predicted alterations in the C terminus of the protein and loss of protein function. The authors developed an antisense oligonucleotide that restored normal AIRE splicing, suggesting a potential treatment approach for these patients. —Melissa L. Norton [ABSTRACT FROM AUTHOR] |
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| Database: |
Complementary Index |
