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.
- Hornig, N. C.
- de Beaufort, C.
- Denzer, F.
- Cools, M.
- Wabitsch, M.
- Ukat, M.
- Kulle, A. E.
- Schweikert, H. U.
- Werner, R.
- Hiort, O.
- Audi, L.
- Siebert, R.
- Ammerpohl, O.
- Holterhus, P. M.
Keywords
- *5' Untranslated Regions
- Androgen-Insensitivity Syndrome/*genetics/metabolism/pathology
- Base Sequence
- Fibroblasts/*metabolism/pathology
- Frameshift Mutation
- Gene Expression Regulation
- Genes, Reporter
- *Germ-Line Mutation
- Humans
- Luciferases/genetics/metabolism
- Male
- Open Reading Frames
- Primary Cell Culture
- *Protein Biosynthesis
- Receptors, Androgen/*genetics/metabolism
- Sequence Analysis, DNA