A deep intronic splice-altering <i>AIRE</i> variant causes APECED syndrome through antisense oligonucleotide-targetable pseudoexon inclusion.

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 dendritic cells and demonstrated that c.1504-818 G>A creates a cryptic splice site and activates

SUBMITTER: Ochoa S 

PROVIDER: S-EPMC12038428 | biostudies-literature | 2024 Sep

REPOSITORIES: biostudies-literature