title: New splice site acceptor mutation in AIRE gene in autoimmune polyendocrine syndrome type 1.
abstract: Autoimmune polyglandular syndrome type 1 (APS-1, OMIM 240300) is a rare autosomal recessive disorder, characterized by the presence of at least two of three major diseases: hypoparathyroidism, Addison's disease, and chronic mucocutaneous candidiasis. We aim to identify the molecular defects and investigate the clinical and mutational characteristics in an index case and other members of a consanguineous family. We identified a novel homozygous mutation in the splice site acceptor (SSA) of intron 5 (c.653-1G>A) in two siblings with different clinical outcomes of APS-1. Coding DNA sequencing revealed that this AIRE mutation potentially compromised the recognition of the constitutive SSA of intron 5, splicing upstream onto a nearby cryptic SSA in intron 5. Surprisingly, the use of an alternative SSA entails the uncovering of a cryptic donor splice site in exon 5. This new transcript generates a truncated protein (p.A214fs67X) containing the first 213 amino acids and followed by 68 aberrant amino acids. The mutation affects the proper splicing, not only at the acceptor but also at the donor splice site, highlighting the complexity of recognizing suitable splicing sites and the importance of sequencing the intron-exon junctions for a more precise molecular diagnosis and correct genetic counseling. As both siblings were carrying the same mutation but exhibited a different APS-1 onset, and one of the brothers was not clinically diagnosed, our finding highlights the possibility to suspect mutations in the AIRE gene in cases of childhood chronic candidiasis and/or hypoparathyroidism otherwise unexplained, especially when the phenotype is associated with other autoimmune diseases.
authors.affiliation: Department of Endocrinology and Nutrition, Hospital Clinic, Barcelona, Spain; Laboratory of Endocrine Disorders, Institut d'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Barcelona, Spain; Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Barcelona, Spain.
authors.forename: Mireia
authors.initials: M
authors.lastname: Mora
authors.affiliation: Department of Endocrinology and Nutrition, Hospital Clinic, Barcelona, Spain; Laboratory of Endocrine Disorders, Institut d'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Barcelona, Spain; Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Barcelona, Spain.
authors.forename: Felicia A
authors.initials: FA
authors.lastname: Hanzu
authors.affiliation: Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Barcelona, Spain; Diabetes and Obesity Research Laboratory - Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Pradas-Juni
authors.affiliation: Department of Endocrinology and Nutrition, Hospital Clinic, Barcelona, Spain; Laboratory of Endocrine Disorders, Institut d'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Barcelona, Spain; Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Barcelona, Spain.
authors.forename: Gloria B
authors.initials: GB
authors.lastname: Aranda
authors.affiliation: Department of Endocrinology and Nutrition, Hospital Clinic, Barcelona, Spain; Laboratory of Endocrine Disorders, Institut d'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Irene
authors.initials: I
authors.lastname: Halperin
authors.affiliation: Department of Endocrinology and Nutrition, Hospital Germans Trias i Pujol Research Institut and Hospital, Universitat Autònoma de Barcelona, Badalona, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Puig-Domingo
authors.affiliation: Department of Internal Medicine, Hospital Clínic, Barcelona, Spain.
authors.forename: Sira
authors.initials: S
authors.lastname: Aguiló
authors.affiliation: Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Barcelona, Spain; Diabetes and Obesity Research Laboratory - Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Fernández-Rebollo
mesh_terms: D001483:Base Sequence; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D016884:Polyendocrinopathies, Autoimmune / Q000235:genetics*; D022821:RNA Splice Sites; D014157:Transcription Factors / Q000235:genetics*; D000096927:AIRE Protein
chemical_list: D022821:RNA Splice Sites; D014157:Transcription Factors; D000096927:AIRE Protein