Science and Research

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 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
Publication details
DOI: 10.1371/journal.pone.0154158
Journal: PloS one
Pages: e0154158 
Number: 4
Work Type: Original
Location: ARCN
Disease Area: LC
Partner / Member: UKSH (Kiel)
Access-Number: 27110943
See publication on PubMed

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