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

作者：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^*

来源：PLos One, 2016, 11(4): e0154158.

DOI：10.1371/journal.pone.0154158

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.

• 出版日期2016-4-25