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

Hornig, Nadine; Beaufort, Carine de; Denzer, Friederike; Cools, Martine; Wabitsch, Martin; Ukat, Martin; Kulle, Alexandra; Schweikert, Hans-Udo; Werner, Ralf; Hiort, Olaf; Audí, Laura; Siebert, Reiner; Ammerpohl, Ole; Holterhus, Paul‐Martin

doi:10.1371/journal.pone.0154158

Cited by 46 publications

(40 citation statements)

References 31 publications

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“…Additional interesting regulatory mechanisms were added to the molecular pathogenesis of DSD, more specifically in the AR gene implicated in androgen insensitivity syndrome (AIS). First, a novel and recurrent 5 ′ untranslated region (5 ′ UTR) mutation was identified, confirming a 20-year-old hypothesis (44). Indeed Mizokami and Chang had previously shown that certain regions of the AR 5 ′ UTR influence induction of translation without having an effect on transcription.…”

Section: Arsupporting

confidence: 55%

“…Functional validation of this variant showed expression of a short polypeptide, reduced levels of normal AR protein, while the mRNA levels remain unchanged. Overall, this is a novel mechanism explaining the complete AIS phenotype in these patients (44). Very recently, Känsäkoski et al identified a deep intronic AR variant (c.2450-118A>G) in two 46,XY sisters with complete AIS by whole-genome sequencing.…”

Section: Armentioning

confidence: 93%

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Non‐coding variation in disorders of sex development

et al. 2017

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Genetic studies in Disorders of Sex Development (DSD), representing a wide spectrum of developmental or functional conditions of the gonad, have mainly been oriented towards the coding genome. Application of genomic technologies, such as whole‐exome sequencing, result in a molecular genetic diagnosis in ∼50% of cases with DSD. Many of the genes mutated in DSD encode transcription factors such as SRY, SOX9, NR5A1, and FOXL2, characterized by a strictly regulated spatiotemporal expression. Hence, it can be hypothesized that at least part of the missing genetic variation in DSD can be explained by non‐coding mutations in regulatory elements that alter gene expression, either by reduced, mis‐ or overexpression of their target genes. In addition, structural variations such as translocations, deletions, duplications or inversions can affect the normal chromatin conformation by different mechanisms. Here, we review non‐coding defects in human DSD phenotypes and in animal models. The wide variety of non‐coding defects found in DSD emphasizes that the regulatory landscape of known and to be discovered DSD genes has to be taken into consideration when investigating the molecular pathogenesis of DSD.

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Section: Arsupporting

confidence: 55%

Section: Armentioning

confidence: 93%

Non‐coding variation in disorders of sex development

et al. 2017

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“…Some of these SNPs are potential candidates for influencing AR activity because they are paralleled by reduced AR protein expression in the corresponding GF cultures, which could explain the lower AR activity in the AIS type II individuals. Interestingly, we previously detected a mutation in the 5′untranslated region of the AR in an individual having CAIS and experimentally showed that this mutation is sufficient to strongly reduce AR protein levels and AR activity (24). This underlines the importance of detection of potential mutations outside the AR -CDS.…”

Section: Discussionmentioning

confidence: 99%

Identification of an AR Mutation-Negative Class of Androgen Insensitivity by Determining Endogenous AR Activity

Hornig

Ukat

Schweikert

et al. 2016

The Journal of Clinical Endocrinology & Metabolism

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Context:Only approximately 85% of patients with a clinical diagnosis complete androgen insensitivity syndrome and less than 30% with partial androgen insensitivity syndrome can be explained by inactivating mutations in the androgen receptor (AR) gene.Objective:The objective of the study was to clarify this discrepancy by in vitro determination of AR transcriptional activity in individuals with disorders of sex development (DSD) and male controls.Design:Quantification of DHT-dependent transcriptional induction of the AR target gene apolipoprotein D (APOD) in cultured genital fibroblasts (GFs) (APOD assay) and next-generation sequencing of the complete coding and noncoding AR locus.Setting:The study was conducted at a university hospital endocrine research laboratory.Patients:GFs from 169 individuals were studied encompassing control males (n = 68), molecular defined DSD other than androgen insensitivity syndrome (AIS; n = 18), AR mutation-positive AIS (n = 37), and previously undiagnosed DSD including patients with a clinical suspicion of AIS (n = 46).Intervention(s):There were no interventions.Main Outcome Measure(s):DHT-dependent APOD expression in cultured GF and AR mutation status in 169 individuals was measured.Results:The APOD assay clearly separated control individuals (healthy males and molecular defined DSD patients other than AIS) from genetically proven AIS (cutoff < 2.3-fold APOD-induction; 100% sensitivity, 93.3% specificity, P < .0001). Of 46 DSD individuals with no AR mutation, 17 (37%) fell below the cutoff, indicating disrupted androgen signaling.Conclusions:AR mutation-positive AIS can be reliably identified by the APOD assay. Its combination with next-generation sequencing of the AR locus uncovered an AR mutation-negative, new class of androgen resistance, which we propose to name AIS type II. Our data support the existence of cellular components outside the AR affecting androgen signaling during sexual differentiation with high clinical relevance.

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“…In contrast, a change of C to T at position +580, that creates an 'ATG' codon and an upstream open reading frame (uORF), was identified in two unrelated individuals with CAIS (Hornig et al 2016). This mutation results in a functional initiation codon and expression of a short polypeptide that impaired translation from the normal downstream ATG and as a consequence, reduced AR protein and activity (Hornig et al 2016). Collectively, these studies suggest that mutations in the promoter and 5'UTR are rare.…”

Section: Clinical Mutations In the 5'utrmentioning

confidence: 98%

Tissue control of androgen action: The ups and downs of androgen receptor expression

Hunter

Hay

Esswein

et al. 2018

Molecular and Cellular Endocrinology

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Please cite this article as: Hunter, I., Hay, C.W., Esswein, B., Watt, K., McEwan, I.J., Tissue control of androgen action: The ups and downs of androgen receptor expression, Molecular and Cellular Endocrinology (2017), doi: 10.1016/j.mce.2017 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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

Cited by 46 publications

References 31 publications

Non‐coding variation in disorders of sex development

Non‐coding variation in disorders of sex development

Identification of an AR Mutation-Negative Class of Androgen Insensitivity by Determining Endogenous AR Activity

Tissue control of androgen action: The ups and downs of androgen receptor expression

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