New splice site acceptor mutation in AIRE gene in autoimmune polyendocrine syndrome type 1.

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...

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Autores principales:	Mireia Mora, Felicia A Hanzu, Marta Pradas-Juni, Gloria B Aranda, Irene Halperin, Manuel Puig-Domingo, Sira Aguiló, Eduardo Fernández-Rebollo
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2014
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/c57a4f8361944501b7b6245ac91216f8
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spelling	oai:doaj.org-article:c57a4f8361944501b7b6245ac91216f82021-11-25T06:09:55ZNew splice site acceptor mutation in AIRE gene in autoimmune polyendocrine syndrome type 1.1932-620310.1371/journal.pone.0101616https://doaj.org/article/c57a4f8361944501b7b6245ac91216f82014-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24988226/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Autoimmune 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.Mireia MoraFelicia A HanzuMarta Pradas-JuniGloria B ArandaIrene HalperinManuel Puig-DomingoSira AguilóEduardo Fernández-RebolloPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 9, Iss 7, p e101616 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Mireia Mora Felicia A Hanzu Marta Pradas-Juni Gloria B Aranda Irene Halperin Manuel Puig-Domingo Sira Aguiló Eduardo Fernández-Rebollo New splice site acceptor mutation in AIRE gene in autoimmune polyendocrine syndrome type 1.
description	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.
format	article
author	Mireia Mora Felicia A Hanzu Marta Pradas-Juni Gloria B Aranda Irene Halperin Manuel Puig-Domingo Sira Aguiló Eduardo Fernández-Rebollo
author_facet	Mireia Mora Felicia A Hanzu Marta Pradas-Juni Gloria B Aranda Irene Halperin Manuel Puig-Domingo Sira Aguiló Eduardo Fernández-Rebollo
author_sort	Mireia Mora
title	New splice site acceptor mutation in AIRE gene in autoimmune polyendocrine syndrome type 1.
title_short	New splice site acceptor mutation in AIRE gene in autoimmune polyendocrine syndrome type 1.
title_full	New splice site acceptor mutation in AIRE gene in autoimmune polyendocrine syndrome type 1.
title_fullStr	New splice site acceptor mutation in AIRE gene in autoimmune polyendocrine syndrome type 1.
title_full_unstemmed	New splice site acceptor mutation in AIRE gene in autoimmune polyendocrine syndrome type 1.
title_sort	new splice site acceptor mutation in aire gene in autoimmune polyendocrine syndrome type 1.
publisher	Public Library of Science (PLoS)
publishDate	2014
url	https://doaj.org/article/c57a4f8361944501b7b6245ac91216f8
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New splice site acceptor mutation in AIRE gene in autoimmune polyendocrine syndrome type 1.

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