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

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

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 readin...

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Main Authors: Hornig, Nadine C., de Beaufort, Carine, Denzer, Friederike, Cools, Martine, Wabitsch, Martin, Ukat, Martin, Kulle, Alexandra E., Schweikert, Hans-Udo, Werner, Ralf, Hiort, Olaf, Audi, Laura, Siebert, Reiner, Ammerpohl, Ole, Holterhus, Paul-Martin
Format: Online
Language:English
Published: Public Library of Science 2016
Online Access:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4844194/
id pubmed-4844194
recordtype oai_dc
spelling pubmed-48441942016-05-05 A Recurrent Germline Mutation in the 5’UTR of the Androgen Receptor Causes Complete Androgen Insensitivity by Activating Aberrant uORF Translation Hornig, Nadine C. de Beaufort, Carine Denzer, Friederike Cools, Martine Wabitsch, Martin Ukat, Martin Kulle, Alexandra E. Schweikert, Hans-Udo Werner, Ralf Hiort, Olaf Audi, Laura Siebert, Reiner Ammerpohl, Ole Holterhus, Paul-Martin Research Article 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. Public Library of Science 2016-04-25 /pmc/articles/PMC4844194/ /pubmed/27110943 http://dx.doi.org/10.1371/journal.pone.0154158 Text en © 2016 Hornig et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
repository_type Open Access Journal
institution_category Foreign Institution
institution US National Center for Biotechnology Information
building NCBI PubMed
collection Online Access
language English
format Online
author Hornig, Nadine C.
de Beaufort, Carine
Denzer, Friederike
Cools, Martine
Wabitsch, Martin
Ukat, Martin
Kulle, Alexandra E.
Schweikert, Hans-Udo
Werner, Ralf
Hiort, Olaf
Audi, Laura
Siebert, Reiner
Ammerpohl, Ole
Holterhus, Paul-Martin
spellingShingle Hornig, Nadine C.
de Beaufort, Carine
Denzer, Friederike
Cools, Martine
Wabitsch, Martin
Ukat, Martin
Kulle, Alexandra E.
Schweikert, Hans-Udo
Werner, Ralf
Hiort, Olaf
Audi, Laura
Siebert, Reiner
Ammerpohl, Ole
Holterhus, Paul-Martin
A Recurrent Germline Mutation in the 5’UTR of the Androgen Receptor Causes Complete Androgen Insensitivity by Activating Aberrant uORF Translation
author_facet Hornig, Nadine C.
de Beaufort, Carine
Denzer, Friederike
Cools, Martine
Wabitsch, Martin
Ukat, Martin
Kulle, Alexandra E.
Schweikert, Hans-Udo
Werner, Ralf
Hiort, Olaf
Audi, Laura
Siebert, Reiner
Ammerpohl, Ole
Holterhus, Paul-Martin
author_sort Hornig, Nadine C.
title A Recurrent Germline Mutation in the 5’UTR of the Androgen Receptor Causes Complete Androgen Insensitivity by Activating Aberrant uORF Translation
title_short A Recurrent Germline Mutation in the 5’UTR of the Androgen Receptor Causes Complete Androgen Insensitivity by Activating Aberrant uORF Translation
title_full A Recurrent Germline Mutation in the 5’UTR of the Androgen Receptor Causes Complete Androgen Insensitivity by Activating Aberrant uORF Translation
title_fullStr A Recurrent Germline Mutation in the 5’UTR of the Androgen Receptor Causes Complete Androgen Insensitivity by Activating Aberrant uORF Translation
title_full_unstemmed A Recurrent Germline Mutation in the 5’UTR of the Androgen Receptor Causes Complete Androgen Insensitivity by Activating Aberrant uORF Translation
title_sort recurrent germline mutation in the 5’utr of the androgen receptor causes complete androgen insensitivity by activating aberrant uorf translation
description 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.
publisher Public Library of Science
publishDate 2016
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4844194/
_version_ 1613570579906953216

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