Androgen insensitivity syndrome (AIS)

SummaryAndrogen insensitivity syndrome in its complete form is a disorder of hormone resistance characterised by a female phenotype in an individual with an XY karyotype and testes producing age-appropriate normal concentrations of androgens. Pathogenesis is the result of mutations in the X-linked androgen receptor gene, which encodes for the ligand-activated androgen receptor—a transcription factor and member of the nuclear receptor superfamily. This Seminar describes the clinical manifestations of androgen insensitivity syndrome from infancy to adulthood, reviews the mechanism of androgen action, and shows examples of how mutations of the androgen receptor gene cause the syndrome. Management of androgen insensitivity syndrome should be undertaken by a multidisciplinary team and include gonadectomy to avoid gonad tumours in later life, appropriate sex-hormone replacement at puberty and beyond, and an emphasis on openness in disclosure

Variable loss of functional activities of androgen receptor mutants in patients with androgen insensitivity syndrome

Androgen receptor (AR) mutations in androgen insensitivity syndrome (AIS) are associated with a variety of clinical phenotypes. The aim of the present study was to compare the molecular properties and potential pathogenic nature of 8 novel and 3 recurrent AR variants with a broad variety of functional assays. Eleven AR variants (p.Cys177Gly, p.Arg609Met, p.Asp691del, p.Leu701Phe, p.Leu723Phe, p.Ser741Tyr, p.Ala766Ser, p.Arg775Leu, p.Phe814Cys, p.Lys913X, p.Ile915Thr) were analyzed for hormone binding, transcriptional activation, cofactor binding, translocation to the nucleus, nuclear dynamics, and structural conformation. Ligand-binding domain variants with low to intermediate transcriptional activation displayed aberrant Kd values for hormone binding and decreased nuclear translocation. Transcriptional activation data, FxxFF-like peptide binding and DNA binding correlated well for all variants, except for p.Arg609Met, p.Leu723Phe and p.Arg775Leu, which displayed a relatively higher peptide binding activity. Variants p.Cys177Gly, p.Asp691del, p.Ala766Ser, p.Phe814Cys, and p.Ile915Thr had intermediate or wild type values in all assays and showed a predominantly nuclear localization in living cells. All transcriptionally inactive variants (p.Arg609Met, p.Leu701Phe, p.Ser741Tyr, p.Arg775Leu, p.Lys913X) were unable to bind to DNA and were associated with complete AIS. Three variants (p.Asp691del, p.Arg775Leu, p.Ile915Thr) still displayed significant functional activities in in vitro assays, although the clinical phenotype was associated with complete AIS. The data show that molecular phenotyping based on 5 different functional assays matched in most (70%) but not all cases. Copyrigh

Passing the Panda Standard: A TAD Off the Mark?

Tilapia, a tropical freshwater fish native to Africa, is an increasingly important global food commodity. The World Wide Fund for Nature (WWF), a major environmental nongovernmental organization, has established stakeholder dialogues to formulate farm certification standards that promote ‘‘responsible’’ culture practices. As a preface to its ‘‘tilapia aquaculture dialogue,’’ the WWF for Nature commissioned a review of potential certification issues, later published as a peer-reviewed article. This article contends that both the review and the draft certification standards subsequently developed fail to adequately integrate critical factors governing the relative sustainability of tilapia production and thereby miss more significant issues related to resource-use efficiency and the appropriation of ecosystem space and services. This raises a distinct possibility that subsequent certification will promote intensive systems of tilapia production that are far less ecologically benign than existing widely practiced semiintensive alternatives. Given the likely future significance of this emergent standard, it is contended that a more holistic approach to certification is essential

Androgen Receptor Function Links Human Sexual Dimorphism to DNA Methylation

Sex differences are well known to be determinants of development, health and disease. Epigenetic mechanisms are also known to differ between men and women through X-inactivation in females. We hypothesized that epigenetic sex differences may also result from sex hormone functions, in particular from long-lasting androgen programming. We aimed at investigating whether inactivation of the androgen receptor, the key regulator of normal male sex development, is associated with differences of the patterns of DNA methylation marks in genital tissues. To this end, we performed large scale array-based analysis of gene methylation profiles on genomic DNA from labioscrotal skin fibroblasts of 8 males and 26 individuals with androgen insensitivity syndrome (AIS) due to inactivating androgen receptor gene mutations. By this approach we identified differential methylation of 167 CpG loci representing 162 unique human genes. These were significantly enriched for androgen target genes and low CpG content promoter genes. Additional 75 genes showed a significant increase of heterogeneity of methylation in AIS compared to a high homogeneity in normal male controls. Our data show that normal and aber

Advocating for Strategic it: Phenomenological Study of Nonprofit it Leaders

Nonprofit organizations (NPOs) lag behind their for-profit and public-sector peers in leveraging IT to satisfy a growing and diverse set of stakeholder expectations. NPO technical debt is attributed to a lack of in-house expertise and financial resources. Despite increasing isomorphic pressures, NPOs have not integrated IT into their organizational strategic planning processes. However, how NPO IT leaders advocate for mission-enhancing IT projects remains under-represented in the literature. This phenomenological study explores the life experiences of those NPO IT leaders as they propose and execute projects within a larger portfolio of competing demands. NPO IT leaders were interviewed from 21 international development and relief service organizations. A total of 56 project experiences were extracted to identify dominant stakeholder relationships, isomorphic requirements, and resource demands. Alternating rounds of interview transcript coding and epoché memos resulted in five representative project vignettes and two leading practice stories. There were four major findings. NPO IT leadership roles are rarely filled by dedicated IT professionals; NPO IT leaders are usually dual-hatted executives. As a result, IT is not integrated into organizational strategic planning processes; NPO IT leaders are often placed in passive and reactionary positions as opposed to ones of strong advocacy. They remain dependent on financial and expertise resources, which confirms that resource dependency theory influences IT strategy. The prominence of end-user requirements in the project experiences marks a shift from previous literature; normative expectations were twice as prevalent as coercive control of funding or legitimacy when driving strategic investments. Further research in NPO IT leadership characteristics (e.g., style, dual-hatted responsibilities, and sex) and the elusiveness of measuring mission-enhancing impact of IT projects should be conducted

Small Business and Employment: A Cross-Sectional Analysis

Politicians within the United States regularly tout the advantages of promoting small business as a means to cure unemployment in the nation’s economy. This paper presents an unbiased cross-sectional study, across all fifty states, of the effects of small business on employment. To affirm for the robustness of our model, we control for industry, geographical region, the proportion of small firms in the state (as a percentage of total firms), gross domestic product, education, and government employment. By eliminating the effects of these other determinants of employment, we were able to conclude that for most industries, the proportion of small businesses in a state has no effect on the unemployment rate

Predicting puberty in partial androgen insensitivity syndrome: Use of clinical and functional androgen receptor indices.

BACKGROUND: PAIS exhibits a complex spectrum of phenotypes and pubertal outcomes. The paucity of reliable prognostic indicators can confound management decisions including sex-of-rearing. We assessed whether external masculinisation score (EMS) at birth or functional assays correlates with pubertal outcome in PAIS patients and whether the EMS is helpful in sex assignment. METHODS: We collected pubertal outcome data for 27 male-assigned PAIS patients, all with confirmed androgen receptor (AR) mutations, including two previously uncharacterized variants (I899F; Y916C). Patients were grouped as follows; EMS at birth <5 and ≥ 5 (EMS in normal males is 12; median EMS in PAIS is 4·7) and pubertal outcomes compared. FINDINGS: Only 6/9 patients (67%) with EMS <5 underwent spontaneous onset of puberty, versus all 18 patients with EMS ≥5 (p = .03). Only 1/6 patients (17%) with EMS <5 developed adult genitalia reaching Tanner stage 4 or 5, versus 11/13 (85%) with EMS ≥5 (p = 0·01). There was no significant difference between the two groups of patients in being prescribed androgen replacement, who reached adult testicular volume ≥ 15 ml, pubic hair Tanner stage 4 or 5, above average adult height, had gynaecomastia, and mastectomy. No correlation was observed between EMS and in vitro AR function. INTERPRETATION: In PAIS with AR mutation, birth EMS is a simple predictor of spontaneous pubertal onset and satisfactory adult genitalia. This provides useful information when discussing the likely options for management at puberty. FUND: European Commission Framework 7 Programme, NIHR Cambridge Biomedical Research Centre, BBSRC DTP

Enrichment of genes either hypo- or hypermethylated in AIS as compared to normal controls.

<p>The bar plots show percentage of loci either located in imprinted genes, genes containing either promoters with high CpG (HCP) or low CpG (LCP) content as well as the percentage of AR target genes as determined by the GATHER tool. Grey bars: percentage of genes present on the array, black bars: percentage of genes hypomethylated and white bars: percentage of genes hypermethylated in AIS patients. p-values have been determined applying χ²-test.</p

Array-based DNA methylation analysis of 26 AIS genital fibroblasts and 8 male control genital fibroblasts.

<p>(A) Supervised cluster analysis of DNA-methylation data obtained from genital fibroblasts separates individuals with AIS (yellow) from male controls (blue) (q<0.04). DNA-methylation is presented on a relative scale. To demonstrate reproducibility all hybridizations performed in duplicates are shown separately. (B) DNA-methylation of APOD (cg05624196) in fibroblasts lacking induction of APOD upon androgen treatment (non-responder) was significantly higher compared to responding fibroblasts (responder). (C) Variability in the DNA-methylation in AIS (yellow) compared to male controls (blue). Green: low, black: medium, red: high avg-beta values. The right bar indicates p-value (F-test).</p

Model of establishment of DNA methylation patterns by AR activity.

<p>(A) Unmutated inactive androgen receptor (AR) binds testosterone (T) activating the receptor. Activated AR binds directly (large arrow) to AR response elements on the DNA inducing gene expression which subsequently prevents DNA methylation (“gene1”). Additionally either the activated AR itself or AR induced genes act on suppressor complexes (S; dotted arrow) which repress particular sets of genes (“gene2”) leading finally to DNA methylation of silenced genes. (B) In AIS missing AR activity prevents activation of AR target genes which might subsequently result to (stochastic <i>de novo</i>) DNA methylation of affected genes. In contrast, genes usually silenced by AR (directly or by additional AR-dependent pathways) become expressed preventing DNA methylation. white lollipops: unmethylated DNA, filled lollipops: methylated DNA.</p