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.
Department of Pediatrics, Division of Pediatric Endocrinology and Diabetes, Christian-Albrechts-University Kiel & University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.|Institute of Human Genetics, Christian-Albrechts-University Kiel & University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
Nadine C
NC
Hornig
Pediatric Clinic, CH de Luxembourg, Luxembourg, GD de Luxembourg.
Carine
C
de Beaufort
Department of Pediatrics, Division of Pediatric Endocrinology and Diabetology, University Ulm, Ulm, Germany.
Friederike
F
Denzer
Department of Pediatrics, Division of Pediatric Endocrinology, Ghent University Hospital and Ghent University, Ghent, Belgium.
Martine
M
Cools
Department of Pediatrics, Division of Pediatric Endocrinology and Diabetology, University Ulm, Ulm, Germany.
Martin
M
Wabitsch
Department of Pediatrics, Division of Pediatric Endocrinology and Diabetes, Christian-Albrechts-University Kiel & University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
Martin
M
Ukat
Department of Pediatrics, Division of Pediatric Endocrinology and Diabetes, Christian-Albrechts-University Kiel & University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
Alexandra E
AE
Kulle
Department of Medicine III, University Bonn, Bonn, Germany.
Hans-Udo
HU
Schweikert
Department of Pediatrics, Division of Experimental Pediatric Endocrinology, University Lübeck, Lübeck, Germany.
Ralf
R
Werner
Department of Pediatrics, Division of Experimental Pediatric Endocrinology, University Lübeck, Lübeck, Germany.
Olaf
O
Hiort
Hospital Vall d'Hebron, Vall d'Hebron Research Institute (VHIR) & Centre for Biomedical Research Network on Rare Diseases (CIBERER), Barcelona, Spain.
Laura
L
Audi
Institute of Human Genetics, Christian-Albrechts-University Kiel & University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
Reiner
R
Siebert
Institute of Human Genetics, Christian-Albrechts-University Kiel & University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
Ole
O
Ammerpohl
Department of Pediatrics, Division of Pediatric Endocrinology and Diabetes, Christian-Albrechts-University Kiel & University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
Paul-Martin
PM
Holterhus
D020121:5' Untranslated Regions; D013734:Androgen-Insensitivity Syndrome / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D001483:Base Sequence; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D016368:Frameshift Mutation; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D018095:Germ-Line Mutation; D006801:Humans; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008297:Male; D016366:Open Reading Frames; D061251:Primary Cell Culture; D014176:Protein Biosynthesis; D011944:Receptors, Androgen / Q000235:genetics* / Q000378:metabolism; D017422:Sequence Analysis, DNA
D020121:5' Untranslated Regions; C410798:AR protein, human; D011944:Receptors, Androgen; D008156:Luciferases