Partial androgen insensitivity syndrome caused by a deep intronic mutation creating an alternative splice acceptor site of the AR gene

Abstract Although partial androgen insensitivity syndrome (PAIS) is caused by attenuated responsiveness to androgens, androgen receptor gene (AR) mutations on the coding regions and their splice sites have been identified only in <25% of patients with a diagnosis of PAIS. We performed extensive m...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Hiroyuki Ono, Hirotomo Saitsu, Reiko Horikawa, Shinichi Nakashima, Yumiko Ohkubo, Kumiko Yanagi, Kazuhiko Nakabayashi, Maki Fukami, Yasuko Fujisawa, Tsutomu Ogata
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/2611bc79154f4c30a9b77384d30d84e1
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:2611bc79154f4c30a9b77384d30d84e1
record_format	dspace
spelling	oai:doaj.org-article:2611bc79154f4c30a9b77384d30d84e12021-12-02T15:08:06ZPartial androgen insensitivity syndrome caused by a deep intronic mutation creating an alternative splice acceptor site of the AR gene10.1038/s41598-018-20691-92045-2322https://doaj.org/article/2611bc79154f4c30a9b77384d30d84e12018-02-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-20691-9https://doaj.org/toc/2045-2322Abstract Although partial androgen insensitivity syndrome (PAIS) is caused by attenuated responsiveness to androgens, androgen receptor gene (AR) mutations on the coding regions and their splice sites have been identified only in <25% of patients with a diagnosis of PAIS. We performed extensive molecular studies including whole exome sequencing in a Japanese family with PAIS, identifying a deep intronic variant beyond the branch site at intron 6 of AR (NM_000044.4:c.2450−42 G > A). This variant created the splice acceptor motif that was accompanied by pyrimidine-rich sequence and two candidate branch sites. Consistent with this, reverse transcriptase (RT)-PCR experiments for cycloheximide-treated lymphoblastoid cell lines revealed a relatively large amount of aberrant mRNA produced by the newly created splice acceptor site and a relatively small amount of wildtype mRNA produced by the normal splice acceptor site. Furthermore, most of the aberrant mRNA was shown to undergo nonsense mediated decay (NMD) and, if a small amount of aberrant mRNA may have escaped NMD, such mRNA was predicted to generate a truncated AR protein missing some functional domains. These findings imply that the deep intronic mutation creating an alternative splice acceptor site resulted in the production of a relatively small amount of wildtype AR mRNA, leading to PAIS.Hiroyuki OnoHirotomo SaitsuReiko HorikawaShinichi NakashimaYumiko OhkuboKumiko YanagiKazuhiko NakabayashiMaki FukamiYasuko FujisawaTsutomu OgataNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-8 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Hiroyuki Ono Hirotomo Saitsu Reiko Horikawa Shinichi Nakashima Yumiko Ohkubo Kumiko Yanagi Kazuhiko Nakabayashi Maki Fukami Yasuko Fujisawa Tsutomu Ogata Partial androgen insensitivity syndrome caused by a deep intronic mutation creating an alternative splice acceptor site of the AR gene
description	Abstract Although partial androgen insensitivity syndrome (PAIS) is caused by attenuated responsiveness to androgens, androgen receptor gene (AR) mutations on the coding regions and their splice sites have been identified only in <25% of patients with a diagnosis of PAIS. We performed extensive molecular studies including whole exome sequencing in a Japanese family with PAIS, identifying a deep intronic variant beyond the branch site at intron 6 of AR (NM_000044.4:c.2450−42 G > A). This variant created the splice acceptor motif that was accompanied by pyrimidine-rich sequence and two candidate branch sites. Consistent with this, reverse transcriptase (RT)-PCR experiments for cycloheximide-treated lymphoblastoid cell lines revealed a relatively large amount of aberrant mRNA produced by the newly created splice acceptor site and a relatively small amount of wildtype mRNA produced by the normal splice acceptor site. Furthermore, most of the aberrant mRNA was shown to undergo nonsense mediated decay (NMD) and, if a small amount of aberrant mRNA may have escaped NMD, such mRNA was predicted to generate a truncated AR protein missing some functional domains. These findings imply that the deep intronic mutation creating an alternative splice acceptor site resulted in the production of a relatively small amount of wildtype AR mRNA, leading to PAIS.
format	article
author	Hiroyuki Ono Hirotomo Saitsu Reiko Horikawa Shinichi Nakashima Yumiko Ohkubo Kumiko Yanagi Kazuhiko Nakabayashi Maki Fukami Yasuko Fujisawa Tsutomu Ogata
author_facet	Hiroyuki Ono Hirotomo Saitsu Reiko Horikawa Shinichi Nakashima Yumiko Ohkubo Kumiko Yanagi Kazuhiko Nakabayashi Maki Fukami Yasuko Fujisawa Tsutomu Ogata
author_sort	Hiroyuki Ono
title	Partial androgen insensitivity syndrome caused by a deep intronic mutation creating an alternative splice acceptor site of the AR gene
title_short	Partial androgen insensitivity syndrome caused by a deep intronic mutation creating an alternative splice acceptor site of the AR gene
title_full	Partial androgen insensitivity syndrome caused by a deep intronic mutation creating an alternative splice acceptor site of the AR gene
title_fullStr	Partial androgen insensitivity syndrome caused by a deep intronic mutation creating an alternative splice acceptor site of the AR gene
title_full_unstemmed	Partial androgen insensitivity syndrome caused by a deep intronic mutation creating an alternative splice acceptor site of the AR gene
title_sort	partial androgen insensitivity syndrome caused by a deep intronic mutation creating an alternative splice acceptor site of the ar gene
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/2611bc79154f4c30a9b77384d30d84e1
work_keys_str_mv	AT hiroyukiono partialandrogeninsensitivitysyndromecausedbyadeepintronicmutationcreatinganalternativespliceacceptorsiteoftheargene AT hirotomosaitsu partialandrogeninsensitivitysyndromecausedbyadeepintronicmutationcreatinganalternativespliceacceptorsiteoftheargene AT reikohorikawa partialandrogeninsensitivitysyndromecausedbyadeepintronicmutationcreatinganalternativespliceacceptorsiteoftheargene AT shinichinakashima partialandrogeninsensitivitysyndromecausedbyadeepintronicmutationcreatinganalternativespliceacceptorsiteoftheargene AT yumikoohkubo partialandrogeninsensitivitysyndromecausedbyadeepintronicmutationcreatinganalternativespliceacceptorsiteoftheargene AT kumikoyanagi partialandrogeninsensitivitysyndromecausedbyadeepintronicmutationcreatinganalternativespliceacceptorsiteoftheargene AT kazuhikonakabayashi partialandrogeninsensitivitysyndromecausedbyadeepintronicmutationcreatinganalternativespliceacceptorsiteoftheargene AT makifukami partialandrogeninsensitivitysyndromecausedbyadeepintronicmutationcreatinganalternativespliceacceptorsiteoftheargene AT yasukofujisawa partialandrogeninsensitivitysyndromecausedbyadeepintronicmutationcreatinganalternativespliceacceptorsiteoftheargene AT tsutomuogata partialandrogeninsensitivitysyndromecausedbyadeepintronicmutationcreatinganalternativespliceacceptorsiteoftheargene
_version_	1718388239818031104

Partial androgen insensitivity syndrome caused by a deep intronic mutation creating an alternative splice acceptor site of the AR gene

Ejemplares similares