Low frequency of androgen receptor gene mutations in 46 XY DSD, and fetal growth restriction

Lek, Ngee; Miles, Harriet L.; Bunch, Trevor; Pilfold-Wilkie, Vickie; Tadokoro-Cuccaro, Rieko; Davies, John Dwyfor; Ong, Ken K.; Hughes, Ieuan A.

doi:10.1136/archdischild-2013-305338

Cited by 36 publications

(23 citation statements)

References 24 publications

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“…These studies confirm that androgens play an important role in growth and development from the fetal period . 46,XY DSDs are a class of diseases, and patients with different causes of 46,XY DSD may have a similar clinical phenotype.…”

supporting

confidence: 62%

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Reference growth data in 46,XY disorders of sex development from a single center

Saenger

2017

Pediatric Investigation

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supporting

confidence: 62%

“…These studies confirm that androgens play an important role in growth and development from the fetal period. 2…”

mentioning

confidence: 99%

Reference growth data in 46,XY disorders of sex development from a single center

Saenger

2017

Pediatric Investigation

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“…In our AR -CDS-negative in AIS type II cohort, we found documented minor syndromic signs in 4 of 46 cases, hence 9%. In addition, prenatal conditions leading to low birth weight may have programming effects on androgen responsiveness of genital cells as a correlation of a low birth weight and a PAIS-like phenotype in individuals without an AR gene mutation has been described before (33). …”

Section: Discussionmentioning

confidence: 98%

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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“…Phe674 (red) falls into a BF3 coactivator interaction surface (green) which is located adjacent to AF2 (orange). striking difference between the two groups was a birth weight which was significantly lower for gestational age in infants with a PAIS phenotype but no AR mutation [68] This provides a simple predictor for the likelihood of finding an AR mutation in PAIS [68]. The observation suggests evidence of placental dysfunction which may cause sub-optimal human Chorionic Gonadotropin (hCG)-stimulated fetal testosterone production during the critical window of fetal male masculinisation as one explanation for the phenotype.…”

Section: Diagnosismentioning

confidence: 96%

Androgen insensitivity syndrome

Mongan

Tadokoro-Cuccaro

Bunch

et al. 2015

Best Practice & Research Clinical Endocrinology & Metab

166

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Low frequency of androgen receptor gene mutations in 46 XY DSD, and fetal growth restriction

Cited by 36 publications

References 24 publications

Reference growth data in 46,XY disorders of sex development from a single center

Reference growth data in 46,XY disorders of sex development from a single center

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

Androgen insensitivity syndrome

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