Male infertility: no evidence of involvement of androgen receptor gene among Indian men

Spermatogenesis is collaboratively controlled by testosterone and follicle stimulating hormone. Testosterone and its immediate metabolite dihydrotestosterone affect their roles through the androgen receptor (AR). Mutations in the AR gene have been shown to cause partial to complete androgen insensitivity or infertility in otherwise normal males. The dependence of germ cells upon Sertoli and Leydig cells for their differentiation into sperms and deletion studies of the AR gene in animal models indicate a direct or indirect role of the AR gene in spermatogenesis. Although a few studies worldwide have reported AR mutations in male infertility, no similar study has been conducted on Indian populations. Therefore, we undertook this study to look at the contribution of AR mutations in male infertility among Indian men. We have sequenced the complete coding region of the AR gene in a total of 399 infertile samples, comprising 277 azoospermic, 100 oligozoospermic, and 22 oligoteratozoospermic samples. A total of 100 healthy males with proven fertility and the same ethnicity as the experimental group served as controls. Sequence analysis revealed no mutation in any of these samples. Our study suggests that mutations in the AR gene are less likely to cause azoospermia and oligozoospermia; however, it was difficult to rule out its effect in oligoteratozoospermia, as the sample size was small

GENETIC CAUSES OF INFERTILITY

SAŽETAK Posljednjih godina došlo je do naglog razvoja dijagnostičkih metoda kojima se može otkriti genetski uzrok neplodnosti, a time procijeniti i rizik prijenosa genetskog poremećaja. Razvojem tehnika potpomognute oplodnje moguće je liječiti veoma teške oblike neplodnosti koji nose značajno veći rizik prijenosa određenih molekularnih promjena na potomstvo. Kod takvih slučajeva veoma je važno otkriti mutacijsku promjenu, jer se time pruža mogućnost davanja precizne genetske informacije o rizicima nasljeđivanja i načina prenatalnog određivanja genotipa ploda. S obzirom na to da ne postoje jedinstvene smjernice u pristupu dijagnostike i liječenja neplodnosti, nastoje se izdvojiti skupine visokorizičnih neplodnih bolesnika prema njihovim kliničkim osobitostima koje će biti podvrgnute rutinskim dijagnostičkim postupcima u svrhu otkrivanja uzroka neplodnosti. Za određene genske poremećaje, kao što su cistična fibroza i sindrom fragilnog X, poznata je uloga u etiopatogenezi neplodnosti. Najnovija molekularna istraživanja genskih mutacija, posebice u β-podjedinici FSH i LH gena, pokazuju svoju dijagnostičku i kliničku vrijednost kod otkrivanja genetskih uzroka neplodnosti.ABSTRACT During the last few years, there is a rapidly expansion of new diagnostic techniques improving the detection of genetic causes of infertility. It is followed by a precise risk assessment of genetic change transmission and possibility to chose the most adequate methode of medically assisted reproduction. The treatment of severe forms of both male and female infertility became possible by the development of very sofisticated in vitro fertilising techniques. Such patients carry the significantly higher risk of having mutational change in one of the disease genes involved in regulation of human reproduction. The detection of mutation in these patients improve the treatment and prognostic assessment in potential future pregnancies. The unique guidelines for the diagnosis and the treatment of infertile couples still doesn’t exist. There are several categories of patients selected by clinical features and associated with some forms of genetic abnormalities. For particular genetic disorders such as cystic fibrosis and fragile X syndrome, their role in pathogenesis of infertility is very well known. Every day, new genetic mutations associated with infertility are discovered. The recent studies involving investigations of significance of molecular mutations, particulary in the gene for the β-subunit of FSH and LH , showed thier diagnostic and clinical value in evaluation both male and female infertility

Association of polymorphisms in genes encoding hormone receptors ESR1, ESR2 and LHCGR with the risk and clinical features of testicular germ cell cancer.

Testicular germ cell cancer (TGCC) is the most common malignancy in young men. Genetic variants known to be associated with risk of TGCC only partially account for the observed familial risks. We aimed to identify additional polymorphisms associated with risk as well as histological and clinical features of TGCC in 367 patients and 214 controls. Polymorphisms in ESR2 (rs1256063; OR=0.53, 95% CI: 0.35-0.79) and LHCGR (rs4597581; OR=0.68, 95% CI: 0.51-0.89, and rs4953617; OR=1.88, 95% CI: 1.21-2.94) associated with risk of TGCC. Polymorphisms in ESR1 (rs9397080; OR=1.85, 95% CI: 1.18-2.91) and LHCGR (rs7371084; OR=2.37, 95% CI: 1.26-4.49) associated with risk of seminoma and metastasis, respectively. SNPs in ESR1 (rs9397080) and LHCGR (rs7371084) were predictors of higher LH levels and higher androgen sensitivity index in healthy subjects. The results suggest that polymorphisms in ESR1, ESR2 and LHCGR contribute to the risk of developing TGCC, histological subtype, and risk to metastasis

Androgen receptor (AR)-CAG trinucleotide repeat length and idiopathic male infertility

CAG trinucleotide repeats in androgen receptor (AR) gene encode a polyglutamine tract in AR N-terminal transactivation domain. Studies have been conducted to evaluate the effect of CAG repeat length on male infertility, which have yielded contradictory results. This study aimed to explore the number of AR-CAG repeats in 150 fertile controls and 150 idiopathic infertile men, divided into four azoospermia, oligozoospermia, asthenozoospermia, and teratozoospermia subgroups. In addition, a meta-analysis was conducted based on previous studies to assess the association of the mentioned variation with male infertility in recent years. Polymerase chain reaction (PCR) targeting followed by an electrophoresis on polyacrylamide gel was used for AR-CAG genotype detecting. Moreover, a systematic search was performed in PubMed, Web of Science, Science Direct, and Google Scholar databases to collect eligible studies for meta-analysis purpose. According to the results, a significant association was observed between increased length of AR-CAG polymorphism and male infertility (p< 0.0001). Furthermore, there were similar significant associations in the azoospermia (p= 0.048), asthenozoospermia (p= 0.013) and teratozoospermia (p= 0.002) subgroups. In addition, meta-analysis on forty studies showed a significant association between AR-CAG polymorphism in the overall analysis (SMD= 0.199, 95 % CI= 0.112-0.287, p<0.001) and the Caucasian subgroup (SMD= 0.151, 95 % CI= 0.040-0.263, p= 0.008). Our results elucidated that long stretches of CAG repeat might lead to AR dysfunction, contributing to male infertility especially in the Caucasian population

Klinische, hormonelle sowie genetische Einflussfaktoren auf die transkriptionsaktivierende Funktion des Androgenrezeptors

Diese Arbeit beschäftigt sich mit klinischen, hormonellen, sowie genetischen Einflussfaktoren auf den ApoD-Assay. Der ApoD-Assay stellt ein Verfahren zur Untersuchung der Androgenrezeptorfunktion dar, indem er in humanen genialen Hautfibroblasten die androgenabhängige Induktion des Androgenrezeptor-Zielgens Apolipoprotein D misst

Androgen Receptor Exon 1 Mutation Causes Androgen Insensitivity by Creating Phosphorylation Site and Inhibiting Melanoma Antigen-A11 Activation of NH 2 - and Carboxyl-terminal Interaction-dependent Transactivation

Naturally occurring germ line mutations in the X-linked human androgen receptor (AR) gene cause incomplete masculinization of the external genitalia by disrupting AR function in males with androgen insensitivity syndrome. Almost all AR missense mutations that cause androgen insensitivity syndrome are located in the highly structured DNA and ligand binding domains. In this report we investigate the functional defect associated with an AR exon 1 missense mutation, R405S, that caused partial androgen insensitivity. The 46,XX heterozygous maternal carrier had a wild-type Arg-405 CGC allele but transmitted an AGC mutant allele coding for Ser-405. At birth, the 46,XY proband had a bifid scrotum, hypospadias, and micropenis consistent with clinical stage 3 partial androgen insensitivity. Androgen-dependent transcriptional activity of AR-R405S expressed in CV1 cells was less than wild-type AR and refractory in androgen-dependent AR NH2- and carboxyl interaction transcription assays that depend on the coregulator effects of melanoma antigen-A11. This mutation created a Ser-405 phosphorylation site evident by the gel migration of an AR-R405S NH2-terminal fragment as a double band that converted to the wild-type single band after treatment with λ-phosphatase. Detrimental effects of the R405S mutation were related to the proximity of the AR WXXLF motif 433WHTLF437 required for melanoma antigen-A11 and p300 to stimulate transcriptional activity associated with the AR NH2- and carboxyl-terminal interaction. We conclude that the coregulator effects of melanoma antigen-A11 on the AR NH2- and carboxyl-terminal interaction amplify the androgen-dependent transcriptional response to p300 required for normal human male sex development in utero

A hotspot for posttranslational modifications on the androgen receptor dimer interface drives pathology and anti-androgen resistance

Mutations of the androgen receptor (AR) associated with prostate cancer and androgen insensitivity syndrome may profoundly influence its structure, protein interaction network, and binding to chromatin, resulting in altered transcription signatures and drug responses. Current structural information fails to explain the effect of pathological mutations on AR structure-function relationship. Here, we have thoroughly studied the effects of selected mutations that span the complete dimer interface of AR ligand-binding domain (AR-LBD) using x-ray crystallography in combination with in vitro, in silico, and cell-based assays. We show that these variants alter AR-dependent transcription and responses to anti-androgens by inducing a previously undescribed allosteric switch in the AR-LBD that increases exposure of a major methylation target, Arg761. We also corroborate the relevance of residues Arg761 and Tyr764 for AR dimerization and function. Together, our results reveal allosteric coupling of AR dimerization and posttranslational modifications as a disease mechanism with implications for precision medicine

Genomic instability and the link to infertility: A focus on microsatellites and genomic instability syndromes.

Infertility is associated to multiple types of different genomic instabilities and is a genetic feature of genomic instability syndromes. While the mismatch repair machinery contributes to the maintenance of genome integrity, surprisingly its potential role in infertility is overlooked. Defects in mismatch repair mechanisms contribute to microsatellite instability and genomic instability syndromes, due to the inability to repair newly replicated DNA. This article reviews the literature to date to elucidate the contribution of microsatellite instability to genomic instability syndromes and infertility. The key findings presented reveal microsatellite instability is poorly researched in genomic instability syndromes and infertility