A Recurrent Germline Mutation in the 5'UTR of the Androgen Receptor Causes Complete Androgen Insensitivity by Activating Aberrant uORF Translation

Autor:	Friederike Denzer, Nadine Hornig, Hans-Udo Schweikert, Olaf Hiort, Ralf Werner, Ole Ammerpohl, Alexandra Kulle, Reiner Siebert, Martine Cools, Martin Ukat, Laura Audí, Carine de Beaufort, Martin Wabitsch, Paul-Martin Holterhus
Jazyk:	angličtina
Rok vydání:	2016
Předmět:	Male 0301 basic medicine Five prime untranslated region Protein Expression Gene Identification and Analysis Gene Expression lcsh:Medicine Gene mutation PHENOTYPE Biochemistry INITIATION Complete androgen insensitivity syndrome Genes Reporter androgen receptor Medicine and Health Sciences 5 UTR TRANSCRIPTION Frameshift Mutation Luciferases lcsh:Science Multidisciplinary general & others [D99] [Human health sciences] Genetics Multidisciplinary Messenger RNA Androgen-Insensitivity Syndrome CANCER Nucleic acids germline mutation Receptors Androgen Androgens Androgen insensitivity syndrome MESSENGER-RNA GENE-MUTATIONS Research Article Multidisciplinaire généralités & autres [D99] [Sciences de la santé humaine] OPEN READING FRAMES Primary Cell Culture Biology Research and Analysis Methods Frameshift mutation Open Reading Frames 03 medical and health sciences Germline mutation GENITAL SKIN FIBROBLASTS Upstream open reading frame Gene Expression and Vector Techniques medicine Humans uORF translation Molecular Biology Techniques Molecular Biology Mutation Detection Germ-Line Mutation SEX DEVELOPMENT Molecular Biology Assays and Analysis Techniques Biology and life sciences Base Sequence IDENTIFICATION lcsh:R Polypeptides Biology and Life Sciences Sequence Analysis DNA Fibroblasts medicine.disease insensivity Hormones Androgen receptor 030104 developmental biology Gene Expression Regulation Protein Biosynthesis Mutation Cancer research RNA Protein Translation lcsh:Q Peptides 5' Untranslated Regions
Zdroj:	PLoS ONE, 11(4). San Franscisco, CA: Public Library of Science (2016). PLoS ONE, Vol 11, Iss 4, p e0154158 (2016) PLOS ONE PLoS ONE
ISSN:	1932-6203
Popis:	A subset of patients with monogenic disorders lacks disease causing mutations in the protein coding region of the corresponding gene. Here we describe a recurrent germline mutation found in two unrelated patients with complete androgen insensitivity syndrome (CAIS) generating an upstream open reading frame (uORF) in the 5' untranslated region (5'-UTR) of the androgen receptor (AR) gene. We show in patient derived primary genital skin fibroblasts as well as in cell-based reporter assays that this mutation severely impacts AR function by reducing AR protein levels without affecting AR mRNA levels. Importantly, the newly generated uORF translates into a polypeptide and the expression level of this polypeptide inversely correlates with protein translation from the primary ORF of the AR thereby providing a model for AR-5'UTR mediated translational repression. Our findings not only add a hitherto unrecognized genetic cause to complete androgen insensitivity but also underline the importance of 5'UTR mutations affecting uORFs for the pathogenesis of monogenic disorders in general.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::c50e2933c1331ce3ffacdb7a20e7ad01 http://orbilu.uni.lu/handle/10993/27172 Zobrazit plný text záznamu