Common Variation in the PIN1 Locus Increases the Genetic Risk to Suffer from Sertoli Cell-Only Syndrome

Funding Information: Funding: This work was supported by the Plan Andaluz de Investigación, Desarrollo e Innovación (PAIDI 2020) (ref. PY20_00212, P20_00583), and the Spanish Ministry of Economy and Competitiveness through the Spanish National Plan for Scientific and Technical Research and Innovation (ref. SAF2016–78722-R, PID2020–120157RB-I00) and the Proyectos I + D + i del Programa Operativo FEDER 2020 (ref. B-CTS-584-UGR20, B-CTS-260-UGR20). FDC was supported by the “Ramón y Cajal” program (ref. RYC-2014–16458), and LBC was supported by the Spanish Ministry of Economy and Competitiveness through the “Juan de la Cierva Incorporación” program (Grant ref. IJC2018– 038026-I, funded by MCIN/AEI/10.13039/501100011033), all of them including FEDER funds. AGJ was funded by MCIN/AEI/10.13039/501100011033 and FSE “El FSE invierte en tu futuro”(grant ref. FPU20/02926). SGM was funded by a previously mentioned project (ref. PY20_00212). IPATIMUP integrates the i3S Research Unit, which is partially supported by the Portuguese Foundation for Science and Technology (FCT), financed by the European Social Funds (COMPETE-FEDER) and National Funds (projects PEstC/SAU/LA0003/2013 and POCI-01–0145-FEDER-007274). AML is funded by the Portuguese Government through FCT (IF/01262/2014). PIM is supported by the FCT post-doctoral fellowship (SFRH/BPD/120777/2016), financed from the Portuguese State Budget of the Ministry for Science, Technology and High Education and from the European Social Fund, available through the Programa Operacional do Capital Humano. ToxOmics—Centre for Toxicogenomics and Human Health, Genetics, Oncology and Human Toxicology, Nova Medical School, Lisbon, is also partially supported by FCT (Projects: UID/BIM/00009/2013 and UIDB/UIDP/00009/2020). SLarriba received support from Instituto de Salud Carlos III (grant DTS18/00101], co-funded by FEDER funds/European Regional Development Fund (ERDF)—a way to build Europe), and from “Generalitat de Catalunya” (grant 2017SGR191). SLarriba is sponsored by the “Researchers Consolidation Program” from the SNS-Dpt. Salut Generalitat de Catalunya (Exp. CES09/020). This article is related to the Ph.D. Doctoral Thesis of Miriam Cerván-Martín (grant ref. BES-2017–081222 funded by MCIN/AEI/10.13039/501100011033 and FSE “El FSE invierte en tu futuro”). Publisher Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland.We aimed to analyze the role of the common genetic variants located in the PIN1 locus, a relevant prolyl isomerase required to control the proliferation of spermatogonial stem cells and the integrity of the blood–testis barrier, in the genetic risk of developing male infertility due to a severe spermatogenic failure (SPGF). Genotyping was performed using TaqMan genotyping assays for three PIN1 taggers (rs2287839, rs2233678 and rs62105751). The study cohort included 715 males diagnosed with SPGF and classified as suffering from non-obstructive azoospermia (NOA, n = 505) or severe oligospermia (SO, n = 210), and 1058 controls from the Iberian Peninsula. The allelic frequency differences between cases and controls were analyzed by the means of logistic regression models. A subtype specific genetic association with the subset of NOA patients classified as suffering from the Sertoli cell-only (SCO) syndrome was observed with the minor alleles showing strong risk effects for this subset (ORaddrs2287839 = 1.85 (1.17–2.93), ORaddrs2233678 = 1.62 (1.11–2.36), ORaddrs62105751 = 1.43 (1.06–1.93)). The causal variants were predicted to affect the binding of key transcription factors and to produce an altered PIN1 gene expression and isoform balance. In conclusion, common non-coding single-nucleotide polymorphisms located in PIN1 increase the genetic risk to develop SCO.publishersversionpublishe

Contribution of TEX15 genetic variants to the risk of developing severe non-obstructive oligozoospermia

Background: Severe spermatogenic failure (SPGF) represents one of the most relevant causes of male infertility. This pathological condition can lead to extreme abnormalities in the seminal sperm count, such as severe oligozoospermia (SO) or non-obstructive azoospermia (NOA). Most cases of SPGF have an unknown aetiology, and it is known that this idiopathic form of male infertility represents a complex condition. In this study, we aimed to evaluate whether common genetic variation in TEX15, which encodes a key player in spermatogenesis, is involved in the susceptibility to idiopathic SPGF.Materials and Methods: We designed a genetic association study comprising a total of 727 SPGF cases (including 527 NOA and 200 SO) and 1,058 unaffected men from the Iberian Peninsula. Following a tagging strategy, three tag single-nucleotide polymorphisms (SNPs) of TEX15 (rs1362912, rs323342, and rs323346) were selected for genotyping using TaqMan probes. Case-control association tests were then performed by logistic regression models. In silico analyses were also carried out to shed light into the putative functional implications of the studied variants.Results: A significant increase in TEX15-rs1362912 minor allele frequency (MAF) was observed in the group of SO patients (MAF = 0.0842) compared to either the control cohort (MAF = 0.0468, OR = 1.90, p = 7.47E-03) or the NOA group (MAF = 0.0472, OR = 1.83, p = 1.23E-02). The genotype distribution of the SO population was also different from those of both control (p = 1.14E-02) and NOA groups (p = 4.33-02). The analysis of functional annotations of the human genome suggested that the effect of the SO-associated TEX15 variants is likely exerted by alteration of the binding affinity of crucial transcription factors for spermatogenesis.Conclusion: Our results suggest that common variation in TEX15 is involved in the genetic predisposition to SO, thus supporting the notion of idiopathic SPGF as a complex trait

Contribution of TEX15 genetic variants to the risk of developing severe non-obstructive oligozoospermia

Lisbon clinical group co-authors and IVIRMA group co-authors Ana Aguiar, (Unidade de Medicina da Reproducao, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Lisboa, Portugal); Carlos Calhaz-Jorge, (Unidade de Medicina da Reproducao, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Lisboa, Portugal); Joaquim Nunes, (Unidade de Medicina da Reproducao, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Lisboa, Portugal); Sandra Sousa (Unidade de Medicina da Reproducao, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Lisboa, Portugal), and Sónia Correia (Centro de Medicina Reprodutiva, Maternidade Alfredo da Costa, Centro Hospitalar Lisboa Central, Lisboa, Portugal); Maria Graça Pinto(Centro de Medicina Reprodutiva, Maternidade Alfredo da Costa, Centro Hospitalar Lisboa Central, Lisboa, Portugal). Alberto Pacheco, (IVIRMA Madrid, Spain); Cristina González, (IVIRMA Sevilla, Spain); Susana Gómez, (IVIRMA Lisboa, Portugal); David Amorós, (IVIRMA Barcelona, Spain); Jesús Aguilar, (IVIRMA Vigo, Spain); Fernando Quintana, (IVIRMA Bilbao, Spain).Background: Severe spermatogenic failure (SPGF) represents one of the most relevant causes of male infertility. This pathological condition can lead to extreme abnormalities in the seminal sperm count, such as severe oligozoospermia (SO) or non-obstructive azoospermia (NOA). Most cases of SPGF have an unknown aetiology, and it is known that this idiopathic form of male infertility represents a complex condition. In this study, we aimed to evaluate whether common genetic variation in TEX15, which encodes a key player in spermatogenesis, is involved in the susceptibility to idiopathic SPGF. Materials and Methods: We designed a genetic association study comprising a total of 727 SPGF cases (including 527 NOA and 200 SO) and 1,058 unaffected men from the Iberian Peninsula. Following a tagging strategy, three tag single-nucleotide polymorphisms (SNPs) of TEX15 (rs1362912, rs323342, and rs323346) were selected for genotyping using TaqMan probes. Case-control association tests were then performed by logistic regression models. In silico analyses were also carried out to shed light into the putative functional implications of the studied variants. Results: A significant increase in TEX15-rs1362912 minor allele frequency (MAF) was observed in the group of SO patients (MAF = 0.0842) compared to either the control cohort (MAF = 0.0468, OR = 1.90, p = 7.47E-03) or the NOA group (MAF = 0.0472, OR = 1.83, p = 1.23E-02). The genotype distribution of the SO population was also different from those of both control (p = 1.14E-02) and NOA groups (p = 4.33–02). The analysis of functional annotations of the human genome suggested that the effect of the SO-associated TEX15 variants is likely exerted by alteration of the binding affinity of crucial transcription factors for spermatogenesis. Conclusion: Our results suggest that common variation in TEX15 is involved in the genetic predisposition to SO, thus supporting the notion of idiopathic SPGF as a complex trait.This work was supported by the Spanish Ministry of Science and Innovation through the Spanish National Plan for Scientific and Technical Research and Innovation (PID 2020-120157RB-I00) and the Andalusian Government through the research projects of “Plan Andaluz de Investigacion, Desarrollo e Innovacion (PAIDI 2020)” (ref. PY20_00212) and “Programa Operativo FEDER 2020” (ref. B-CTS-584-UGR20). LB-C was supported by the Spanish Ministry of Science and Innovation through the “Juan de la Cierva Incorporacion” program (Grant ref. IJC 2018-038026- I, funded by MCIN/AEI/10.13039/501100011033), which includes FEDER funds. AG-J was funded by MCIN/AEI/ 10.13039/501100011033 and FSE “El FSE invierte en tu futuro” (grant ref. FPU20/02926). IPATIMUP integrates the i3S Research Unit, which is partially supported by the Portuguese Foundation for Science and Technology (FCT), financed by the European Social Funds (COMPETE-FEDER) and National Funds (projects PEstC/SAU/LA0003/2013 and POCI-01-0145-FEDER-007274). PM is supported by the FCT post-doctoral fellowship (SFRH/BPD/120777/2016), financed from the Portuguese State Budget of the Ministry for Science, Technology and High Education and from the European Social Fund, available through the Programa Operacional do Capital Humano. ToxOmics—Centre for Toxicogenomics and Human Health, Genetics, Oncology and Human Toxicology, Nova Medical School, Lisbon, is also partially supported by FCT (UID/BIM/00009/2016 and UIDB/00009/2020). SL received support from Instituto de Salud Carlos III (grant: DTS18/00101], co-funded by FEDER funds/European Regional Development Fund (ERDF)-a way to build Europe-), and from “Generalitat de Catalunya” (grant 2017SGR191). SL is sponsored by the “Researchers Consolidation Program” from the SNS-Dpt. Salut Generalitat de Catalunya (Exp. CES09/020). This article is related to the Ph.D. Doctoral Thesis of AG-J.info:eu-repo/semantics/publishedVersio

Constrained SUSY seesaws with a 125 GeV Higgs

Motivated by the ATLAS and CMS discovery of a Higgs-like boson with a mass around 125 GeV, and by the need of explaining neutrino masses, we analyse the three canonical SUSY versions of the seesaw mechanism (type I, II and III) with CMSSM boundary conditions. In type II and III cases, SUSY particles are lighter than in the CMSSM (or the constrained type I seesaw), for the same set of input parameters at the universality scale. Thus, to explain $m_{h^0} \simeq 125 GeV$ at low energies, one is forced into regions of parameter space with very large values of $m_0$, $M_{1/2}$ or $A_0$. We compare the squark and gluino masses allowed by the ATLAS and CMS ranges for $m_{h^0}$ (extracted from the 2011-2012 data), and discuss the possibility of distinguishing seesaw models in view of future results on SUSY searches. In particular, we briefly comment on the discovery potential of LHC upgrades, for squark/gluino mass ranges required by present Higgs mass constraints. A discrimination between different seesaw models cannot rely on the Higgs mass data alone, therefore we also take into account the MEG upper limit on BR$(\mu \to e \gamma)$ and show that, in some cases, this may help to restrict the SUSY parameter space, as well as to set complementary limits on the seesaw scale.Comment: 28 pages, 7 figures. v2: comments and references added. Final version to appear in JHE

Immune and spermatogenesis-related loci are involved in the development of extreme patterns of male infertility

We conducted a genome-wide association study in a large population of infertile men due to unexplained spermatogenic failure (SPGF). More than seven million genetic variants were analysed in 1,274 SPGF cases and 1,951 unaffected controls from two independent European cohorts. Two genomic regions were associated with the most severe histological pattern of SPGF, defined by Sertoli cell-only (SCO) phenotype, namely the MHC class II gene HLA-DRB1 (rs1136759, P = 1.32E-08, OR = 1.80) and an upstream locus of VRK1 (rs115054029, P = 4.24E-08, OR = 3.14), which encodes a protein kinase involved in the regulation of spermatogenesis. The SCO-associated rs1136759 allele (G) determines a serine in the position 13 of the HLA-DR beta 1 molecule located in the antigen-binding pocket. Overall, our data support the notion of unexplained SPGF as a complex trait influenced by common variation in the genome, with the SCO phenotype likely representing an immune-mediated condition. A GWAS in a large case-control cohort of European ancestry identifies two genomic regions, the MHC class II gene HLA-DRB1 and an upstream locus of VRK1, that are associated with the most severe phenotype of spermatogenic failure

Nucleophile-Catalyzed Additions to Activated Triple Bonds. Protection of Lactams, Imides, and Nucleosides with MocVinyl and Related Groups

Additions of lactams, imides, (S)-4-benzyl-1,3-oxazolidin-2-one, 2-pyridone, pyrimidine-2,4-diones (AZT derivatives), or inosines to the electron-deficient triple bonds of methyl propynoate, tert-butyl propynoate, 3-butyn-2-one, N-propynoylmorpholine, or N-methoxy-N-methylpropynamide in the presence of many potential catalysts were examined. DABCO and, second, DMAP appeared to be the best (highest reaction rates and E/Z ratios), while RuCl3, RuClCp*(PPh3)2, AuCl, AuCl(PPh3), CuI, and Cu2(OTf)2 were incapable of catalyzing such additions. The groups incorporated (for example, the 2-(methoxycarbonyl)ethenyl group that we name MocVinyl) serve as protecting groups for the above-mentioned heterocyclic CONH or CONHCO moieties. Deprotections were accomplished via exchange with good nucleophiles: the 1-dodecanethiolate anion turned out to be the most general and efficient reagent, but in some particular cases other nucleophiles also worked (e.g., MocVinyl-inosines can be cleaved with succinimide anion). Some structural and mechanistic details have been accounted for with the help of DFT and MP2 calculations