Dataset Information

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

ABSTRACT:

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.

SUBMITTER: Hornig NC

PROVIDER: S-EPMC5095254 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Hornig N C NC Ukat M M Schweikert H U HU Hiort O O Werner R R Drop S L S SL Cools M M Hughes I A IA Audi L L Ahmed S F SF Demiri J J Rodens P P Worch L L Wehner G G Kulle A E AE Dunstheimer D D Müller-Roßberg E E Reinehr T T Hadidi A T AT Eckstein A K AK van der Horst C C Seif C C Siebert R R Ammerpohl O O Holterhus P-M PM

The Journal of clinical endocrinology and metabolism 20160901 11

<h4>Context</h4>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.<h4>Objective</h4>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.<h4>Design</h4>Quantification of D ...[more]

PMID: 27583472

Similar Datasets

Project description:BackgroundAndrogen insensitivity syndrome (AIS) is caused by abnormal androgen receptor (AR) genes that show variable genotypes and phenotypes. However, the correlation between genotype and phenotype is unclear.MethodsWe retrospectively evaluated 64 patients with AIS at Shanghai Children's Hospital from 2015 to 2022. We analysed the clinical data of the patients, including hormone levels, AR gene variants, and functional domains.ResultsVariants occurred in the 3 major functional domains in 56 patients, including 23 patients with complete androgen insensitivity syndrome (CAIS) and 33 with partial androgen insensitivity syndrome (PAIS). The incidence of nonscrotal fusion (P = 0.019) and proximal urethral opening (P = 0.0002) in the ligand-binding domain (LBD) group was higher than that in the non-LBD group. The phallus length in the LBD group was significantly shorter than that in the non-LBD group (P = 0.009). The external masculinization score (EMS) in the LBD group was significantly lower than that in the non-LBD group (P = 0.013). The levels of inhibin-B (INHB; P = 0.0007), basal luteinizing hormone (LH; P = 0.033), LH peak (P = 0.002), and testosterone (T) after human chorionic gonadotropin (HCG) stimulation (P = 0.001) in the LBD group were higher than those in the non-LBD group. There were 53 variants in 64 patients, including 42 reported and 11 novel AR variants, including p.Met247Arg, p.Asp266Glyfs*39, p.Arg362Serfs*140, p.Ala385Val, p.Glu541Asp, p.Pro613Leu, p.Pro695Leu, p.Asn757Asp, c.1616 + 1dup, c.1886-1G > A and exon 5-7 deletion.ConclusionsThe EMS of patients with AIS in the LBD group was significantly lower than that in the non-LBD group. The phallus length was shorter, and the incidences of proximal urethral opening and nonscrotal fusion were higher, suggesting that the phenotypes in the LBD group were more severe. The levels of INHB, basal LH, peak LH, and T after HCG stimulation in the LBD group were higher than those in the non-LBD group, suggesting that androgen resistance in the LBD group was more severe. We identified 53 variants in 64 patients: 42 reported and 11 novel AR variants. These findings provide new and deeper insight into AIS diagnosis and genetic assessment of AIS.

Dataset Information

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

Context

Objective

Design

Setting

Patients

Intervention(s)

Main outcome measure(s)

Results

Conclusions

Publications

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

Similar Datasets

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