Transcriptome analysis of the adult human Klinefelter testis and cellularity-matched controls reveals disturbed differentiation of Sertoli- and Leydig cells article

AbstractThe most common human sex chromosomal disorder is Klinefelter syndrome (KS; 47,XXY). Adult patients with KS display a diverse phenotype but are nearly always infertile, due to testicular degeneration at puberty. To identify mechanisms causing the selective destruction of the seminiferous epithelium, we performed RNA-sequencing of 24 fixed paraffin-embedded testicular tissue samples. Analysis of informative transcriptomes revealed 235 differentially expressed transcripts (DETs) in the adult KS testis showing enrichment of long non-coding RNAs, but surprisingly not of X-chromosomal transcripts. Comparison to 46,XY samples with complete spermatogenesis and Sertoli cell-only-syndrome allowed prediction of the cellular origin of 71 of the DETs. DACH2 and FAM9A were validated by immunohistochemistry and found to mark apparently undifferentiated somatic cell populations in the KS testes. Moreover, transcriptomes from fetal, pre-pubertal, and adult KS testes showed a limited overlap, indicating that different mechanisms are likely to operate at each developmental stage. Based on our data, we propose that testicular degeneration in men with KS is a consequence of germ cells loss initiated during early development in combination with disturbed maturation of Sertoli- and Leydig cells.</jats:p

Genome-wide assessment of the association of rare and common copy number variations to testicular germ cell cancer.

Testicular germ cell cancer (TGCC) is one of the most heritable forms of cancer. Previous genome-wide association studies have focused on single nucleotide polymorphisms (SNPs), largely ignoring the influence of copy number variants (CNVs). Here we present a genome-wide study of copy number variation on a cohort of 212 cases and 437 controls from Denmark, which was genotyped at ~1.8 million markers, half of which were non-polymorphic copy number markers. No association of common variants were found, whereas analysis of rare variants (present in less than 1% of the samples) initially indicated a single gene with significantly higher accumulation of rare CNVs in cases as compared to controls, at the gene PTPN1 (P=3.8*10-2, 0.9% of cases and 0% of controls). However, the CNV could not be verified by qPCR in the affected samples. The CNV calling of the array data was validated by sequencing of the GSTM1 gene, which showed that the CNV frequency was in complete agreement between the two platforms. This study therefore disconfirms the hypothesis that there exists a single CNV locus with a major effect size that predisposes to TGCC. Genome-wide pathway association analysis indicated a weak association of rare CNVs related to cell migration (FDR=0.021, 1.8% of cases and 1.1% of controls). Dysregulation during migration of primordial germ cells has previously been suspected to be a part of TGCC development and this set of multiple rare variants may thereby have a minor contribution to an increased susceptibility of TGCCs

Pituitary–gonadal hormones associated with respiratory failure in men and women hospitalized with COVID-19: an observational cohort study

Aim: To explore pituitary–gonadal hormone concentrations and assess their association with inflammation, severe respiratory failure, and mortality in hospitalized men and women with COVID-19, and compare these to hormone concentration s in hospitalized patients with bacterial community-acquired pneumonia (CAP) and influenza virus CAP and to concentrations in a reference group of healthy individuals. Methods: Serum concentrations of testosterone, estrone sulfate, luteini zing hormone (LH), follicle-stimulating hormone (FSH), and interleukin-6 (IL-6) were measured within 4 days of admission. Associations were assessed by logistic regression analysis in patients with COVID-19, and results were reported as odds ratio with 95% CI per two-fold reduction after adjustment for age, comorbidities, days to sample collection, and IL-6 concentrations. Results: In total, 278 patients with COVID-19, 21 with influenza virus CA P, and 76 with bacterial CAP were included. Testosterone concentrations were suppressed in men hospitalized with COVID-19, bacterial and influenza virus CA P, and moderately suppressed in women. Reductions in testosterone (OR: 3.43 (1.14–10.30), P = 0.028) and LH (OR: 2.51 (1.28–4.92), P = 0.008) were associated with higher odds of mehanical ventilation (MV) in men with COVID-19. In women with COVID-19, reductions in LH (OR: 3.34 (1.02–10-90), P = 0.046) and FSH (OR: 2.52 (1.01–6.27), P = 0.047) were associated with higher odds of MV. Conclusion: Low testosterone and LH concentrations were predictive of severe respiratory failure in men with COVID-19, whereas low concentrations of LH and FSH were predictive of severe respiratory failure in women with COVID-19