Reference : A Recurrent Germline Mutation in the 5'UTR of the Androgen Receptor Causes Complete A...
Scientific journals : Article
Human health sciences : Multidisciplinary, general & others
A Recurrent Germline Mutation in the 5'UTR of the Androgen Receptor Causes Complete Androgen Insensitivity by Activating Aberrant uORF Translation
Hornig, N.C. []
De Beaufort, Carine mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > >]
Denzer, F. []
Cools, M. []
Wabitsch []
Ukat, M. []
Kulle, A.E. []
Schweikert, H.U. []
Werner, R. []
Hiort, O. []
Audi, L. []
Siebert, R. []
Ammerpohl, O. []
Holterhus, P.M. []
Public Library of Science
eCollection 2016
Yes (verified by ORBilu)
San Franscisco
[en] germline mutation ; 5 UTR ; androgen receptor ; insensivity ; uORF translation
[en] 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.

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hornig et al. 2016 recurrent germline mutation.PDFPublisher postprint1.28 MBView/Open

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