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Up-regulated microRNAs in blastocoel fluid of human implanted embryos could control circuits of pluripotency and be related to embryo competence

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JOURNAL OF ASSISTED REPRODUCTION AND genetICS 2025年 1-15页

作者： Battaglia, Rosalia Caponnetto, Angela Ferrara, Carmen Fazzio, Anna Barbagallo, Cristina Stella, Michele Barbagallo, Davide Ragusa, Marco Vento, Maria Elena Borzi, Placido Scollo, Paolo Carli, Luca Feichtinger, Michael Kasapi, Evangelia Tsakos, Elias Palini, Simone Sierka, Wojciech Pecorino, Basilio Campitiello, Maria Rosaria Ronsini, Carlo Purrello, Michele Valerio, Domenico Longobardi, Salvatore D'Hooghe, Thomas Di Pietro, Cinzia Univ Catania Dept Biomed & Biotechnol Sci Sect Biol & Genet G Sichel I-95123 Catania Italy Univ Enna Kore Dept Med & Surg I-94100 Enna Italy Cannizzaro Hosp IVF Unit Catania Italy Wunschbaby Inst Feichtinger Vienna Austria EmbryoClin IVF Thessaloniki Greece Cervesi Hosp IVF Unit Cattolica Italy Gyncentrum Sp Zelazna 1 PL-40851 Katowice Poland ASL Salerno Dept Obstet & Gynecol & Physiopathol Human Reprod Salerno Italy Univ Campania Luigi Vanvitelli Dept Woman Child & Gen & Specialized Surg Naples Italy Inst Genet Res IRG I-80143 Naples Italy Merck Serono SpA Global Clin Dev Rome Italy Merck KGaA Darmstadt Germany KU Leuven Univ Leuven Dept Dev & Regenerat Biomed Sci Grp Leuven Belgium

Purpose The paper aims to investigate the biological role of microRNAs secreted by preimplantation embryo into the blastocoel fluid and to detect a distinctive molecular signature for identifying embryos with the highest implantation potential. Methods We carried on a multicenter retrospective study involving five European IVF centers. We collected 112 blastocoel fluid samples from embryos on day 5 post-fertilization, cultured individually, along with data on blastocyst grade and embryo transfer outcomes. Using a custom TLDA Array, we compared the expression levels of 89 miRNAs between 33 fluids from high-quality implanted embryos and 30 fluids from high-quality not-implanted embryos. Expression differences were assessed using SAM and t-test. Additionally, correlation and function enrichment analysis and network construction were conducted to identify the biological roles of deregulated microRNAs. results We identified six up-regulated microRNAs in the blastocoel fluid from implanted embryos, significantly and positively correlated across all samples (r >= 0.7;P <= 0.05). They could take part in pluripotency circuits, regulating and being regulated by transcription factors associated with stemness, cell growth, and embryo development. The ROC curve analysis confirmed the potential of these miRNAs as implantation classifiers. Conclusion The six miRNAs up-regulated in blastocoel fluid from implanted embryos may represent a functional molecular signature for evaluating blastocyst quality and identifying the most competent embryos. Their evaluation associated with non-invasive preimplantation genetic testing, integrating epigenetic and genomic analyses, could enhance implantation grade and allow for identification of the euploid embryo not able to implant.

关键词： Blastocoel fluid Embryo development Embryo implantation Human blastocyst MicroRNAs

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Mechanism of Catalysis and Substrate Binding of Epoxyqueuosine Reductase in the Biosynthetic Pathway to Queuosine-Modified tRNA

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BIOCHEMISTRY 2024年第2期64卷 458-467页

作者： Hu, You Jaroch, Marshall Sun, Guangxin Dedon, Peter C. de Crecy-Lagard, Valerie Bruner, Steven D. Univ Florida Dept Chem Gainesville FL 32611 USA Univ Florida Dept Microbiol & Cell Sci Gainesville FL 32611 USA MIT Dept Biol Engn Cambridge MA 02139 USA Singapore MIT Alliance Res & Technol Antimicrobial Resistance IRG Singapore 138602 Singapore Univ Florida Genet Inst Gainesville FL 32611 USA

Post-transcriptional modifications at the anticodon stem-loop of tRNAs are key to the translation function. Metabolic pathways to these modifications often incorporate complex enzymology. A notable example is the hypermodified nucleoside, queuosine, found at the wobble position of Asn, Asp, His, and Tyr encoding tRNAs. The epoxyqueuosine reductase, QueH, catalyzes the final step in the biosynthetic pathway to queuosine. The metalloenzyme catalyzes a two-electron reduction of epoxyqueuosine to provide the modified tRNA. The structure of QueH from T. maritima has previously been determined and unexpectedly contains two metal binding motifs in the active site. This includes a predicted 4Fe-4S cluster, along with a single-metal binding site coordinated by two cysteines along an aspartate carboxylate. In this report, we describe the structural and biochemical analysis of the QueH metal binding sites along with the chemistry of epoxide deoxygenation. To probe the active-site architecture, enzyme mutants of metal binding residues were structurally and biochemically characterized. In addition, structural and binding experiments were used to probe interactions of QueH with tRNA and the in vivo role of QueH and variants in Q-tRNA synthesis was evaluated. Overall, this work provides insight into the chemical mechanism of the final step of the queuosine biosynthetic pathway.

关键词： Catalysis

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Down-regulation of long non-coding RNAs in reproductive aging and analysis of the lncRNA-miRNA-mRNA networks in human cumulus cells

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JOURNAL OF ASSISTED REPRODUCTION AND genetICS 2022年第4期39卷 919-931页

作者： Caponnetto, Angela Battaglia, Rosalia Ferrara, Carmen Vento, Maria Elena Borzi, Placido Paradiso, Marianna Scollo, Paolo Purrello, Michele Longobardi, Salvatore D'Hooghe, Thomas Valerio, Domenico Di Pietro, Cinzia Univ Catania Dept Biomed & Biotechnol Sci Sect Biol & Genet Giovanni Sichel I-95123 Catania Italy Cannizzaro Hosp IVF Unit Catania Italy Merck Serono SpA Global Clin Dev Rome Italy Healthcare Business Merck KGaA R&D Healthcare Global Med Affairs Fertil Frankfurter Str 250 D-64293 Darmstadt Germany Inst Genet Res IRG I-80143 Naples Italy

Purpose Long non-coding RNAs (lncRNAs) control gene expression at multiple levels. By interacting with microRNAs (miRNAs), they regulate their mRNA targets creating dynamic regulatory networks involved in different cellular processes. Their role in follicle development and oocyte maturation has recently emerged. lncRNA deregulation has been found associated with different pathological conditions. In this study, we identified differentially expressed lncRNAs in cumulus cells (CCs) isolated from MII oocytes of advanced maternal age women and proposed ceRNA-networks involved in signaling pathways crucial in ovarian folliculogenesis and female germ cell maturation. Methods We performed a high-throughput analysis of the expression profile of 68 lncRNAs from CCs of aged and young women by using NanoString technology. By miRNet, TarPmiR, miRTarBase, OKdb, and KEGG we predicted some ceRNA-networks involving the differentially expressed (DE) lncRNAs, miRNA interactors, and their mRNA target genes. results We identified 28 lncRNAs down-regulated in CC samples from aged women. The analysis revealed that the miRNAs binding 11 of the DE lncRNAs and their mRNA targets are included in ceRNA-networks involved in the regulation of the PI3K-Akt, FOXO, and p53 signaling pathways. Conclusion We proposed that the lncRNA down-regulation in CCs from aged women could influence the expression of genes encoding proteins deregulated in reproductive aging. A better understanding of the interplay of lncRNA-miRNA-mRNA networks in human CCs could increase our knowledge about the mechanisms of regulation of gene expression involved in aging, lead to the development of novel therapeutics, and improve reproductive outcomes in aged women.

关键词： Regulation of gene expression lncRNAs Cumulus cells Reproductive aging ceRNA-networks

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A Proteomics Approach to Profiling the Temporal Translational response to Stress and Growth

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ISCIENCE 2018年第November 30, 2018期9卷 367-+页

作者： Rothenberg, Daniel A. Taliaferro, J. Matthew Huber, Sabrina M. Begley, Thomas J. Dedon, Peter C. White, Forest M. MIT Dept Biol Engn 77 Massachusetts Ave Cambridge MA 02139 USA MIT Koch Inst Integrat Canc Res 77 Massachusetts Ave Cambridge MA 02139 USA MIT Dept Biol 77 Massachusetts Ave Cambridge MA 02139 USA Univ Colorado Dept Biochem & Mol Genet Sch Med Aurora CO 80045 USA Univ Colorado RNA Biosci Initiat Sch Med Aurora CO 80045 USA SUNY Albany Coll Nanoscale Sci & Engn Albany NY 12203 USA Singapore MIT Alliance Res & Technol Infect Dis IRG Singapore Singapore MIT Ctr Precis Canc Med 77 Massachusetts Ave Cambridge MA 02139 USA

To quantify dynamic protein synthesis rates, we developed MITNCAT, a method combining multiplexed isobaric mass tagging with pulsed SILAC (pSILAC) and bio-orthogonal non-canonical amino add tagging (BONCAT) to label newly synthesized proteins with azidohomoalanine (Aha), thus enabling high temporal resolution across multiple conditions in a single analysis. MITNCAT quantification of protein synthesis rates following induction of the unfolded protein response revealed global down-regulation of protein synthesis, with stronger down-regulation of glycolytic and protein synthesis machinery proteins, but up-regulation of several key chaperones. Waves of temporally distinct protein synthesis were observed in response to epidermal growth factor, with altered synthesis detectable in the first 15 min. Comparison of protein synthesis with mRNA sequencing and ribosome footprinting distinguished protein synthesis driven by increased transcription versus increased translational efficiency. Temporal delays between ribosome occupancy and protein synthesis were observed and found to correlate with altered codon usage in significantly delayed proteins.

关键词： Functional Aspects of Cell Biology Methodology in Biological Sciences Proteomics

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HUMAN REPRODUCTION 2021年第5期36卷 1310-1325页

作者： Dell'Aversana, C. Cuomo, F. Longobardi, S. D'Hooghe, T. Caprio, F. Franci, G. Santonastaso, M. Colacurci, N. Barone, S. Pisaturo, V Valerio, D. Altucci, L. Univ Campania Luigi Vanvitelli Dept Precis Med I-80138 Naples Italy Natl Res Council CNR Inst Expt Endocrinol & Oncol Gaetano Salvatore IE I-80131 Naples Italy EPI C Srl I-80138 Naples Italy Merck KGaA D-64293 Darmstadt Germany Univ Campania Luigi Vanvitelli Outpatient Fertil Unit I-80138 Naples Italy Univ Salerno ScuolaMed Salernitana Dept Med Surg & Dent I-84081 Baronissi SA Italy Univ Campania Luigi Vanvitelli Dept Woman Child & Gen & Special Surg I-80138 Naples Italy Versilia Hosp Dept Assisted Reprod I-55049 Lido Di Camaiore Lucca Italy Int Evangel Hosp Dept Reprod Med I-16122 Genoa Italy Merck Serono SpA I-00176 Rome Italy Inst Genet Res IRG I-80143 Naples Italy

STUDY QUESTION: Is the microRNA (miRNA) expression pattern of cumulus oophorus cells (COCs) in women undergoing medically assisted reproduction (MAR) procedures differentially modulated according to patient age and gonadotropin treatment strategy? SUMMARY ANSWER: Maternal age is an independent factor impacting miRNA expression in COCs while gonadotropin treatment may affect follicular miRNA expression and IVF efficacy. WHAT IS KNOWN ALREADY: Epigenetic mechanisms in female infertility are complex and poorly studied. DNA methylation, histone modifications, miRNAs and nucleosome positioning influence cellular machinery through positive and negative feedback mechanisms either alone or interactively. miRNAs are important regulators during oogenesis, spermatogenesis and early embryogenesis, and are reported to play a role in regulating crosstalk between the oocyte and COCs. Although miRNome analysis has been performed in female human reproductive tissues (endometrium, myometrium, cervix and ovaries), epigenetic modifications in women with infertility have not been explored in detail. In addition, the impact of gonadotropin treatments during MAR on miRNA expression in COCs has not been fully investigated. STUDY DESIGN, SIZE, DURATION: This study was carried out in 53 COC samples obtained from mature metaphase II (MII) oocytes in 53 women undergoing MAR treatment A total of 38 samples for assay development were pooled by maternal age and gonadotropin treatment into four predetermined subgroups: >= 36 years and recombinant human FSH (r-hFSH), n = 10;>= 36 years and r-hFSH+ recombinant human-luteinizing hormone (r-hLH), n = 10;<= 35 years and r-hFSH, n = 9;<= 35 years and r-hFSH+r-hLH, n = 9. miRNome profiles were determined and compared between subgroups. Expression of defined miRNAs was validated in the remaining fifteen samples, representative of each subgroup, by quantitative polymerase chain reaction (PCR). PARTICIPANTS/MATERIALS, SETTING, METHODS: COCs were processed f

关键词： miRNA epigenetics gonadotropin stimulation aging cumulus oophorus cells medically assisted reproduction

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Genome-first approach for the characterization of a complex phenotype with combined NBAS and CUL4B deficiency

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BONE 2020年 140卷 115571-115571页

作者： Ritelli, Marco Palagano, Eleonora Cinquina, Valeria Beccagutti, Federica Chiarelli, Nicola Strina, Dario Hall, Ignacio Fernando Villa, Anna Sobacchi, Cristina Colombi, Marina Univ Brescia Dept Mol & Translat Med Div Biol & Genet Viale Europa 11 I-25123 Brescia Italy CNR Milan Unit Ist Ric Genet & Biomed CNR IRG I-20138 Milan Italy Ist Ricovero & Cura Carattere Sci IRCCS Humanitas Clin & Res Ctr Via Manzoni 56 I-20089 Rozzano Italy Fdn Poliambulanza Dept Neonatal Intens Care I-25124 Brescia Italy Humanitas Univ I-20089 Rozzano Italy IRCCS San Raffaele Sci Inst San Raffaele Telethon Inst Gene Therapy SR Tiget I-20132 Milan Italy Natl Res Council CNR IBBR Inst Biosci & BioResources Div Florence I-50019 Sesto Fiorentino Italy

Biallelic variants in neuroblastoma-amplified sequence (NBAS) cause an extremely broad spectrum of phenotypes. Clinical features range from isolated recurrent episodes of liver failure to multisystemic syndrome including short stature, skeletal osteopenia and dysplasia, optic atrophy, and a variable immunological, cutaneous, muscular, and neurological abnormalities. Hemizygous variants in CUL4B cause syndromic X-linked intellectual disability characterized by limitations in intellectual functions, developmental delays in gait, cognitive, and speech functioning, and other features including short stature, dysmorphism, and cerebral malformations. In this study, we report on a 4.5-month-old preterm infant with a complex phenotype mainly characterized by placental-related severe intrauterine growth restriction, post-natal growth failure with spontaneous bone fractures, which led to a suspicion of osteogenesis imperfecta, and lethal bronchopulmonary dysplasia with pulmonary hypertension. Whole exome sequencing identified compound heterozygosity for a known frameshift and a novel missense variant in NBAS and hemizygosity for a known CUL4B nonsense mutation. In vitro functional studies on the novel NBAS missense substitution demonstrated altered Golgi-to-endoplasmic reticulum retrograde vesicular trafficking and reduced collagen secretion, likely explaining part of the patient's phenotype. We also provided a comprehensive overview of the phenotypic features of NBAS and CUL4B deficiency, thus updating the recently emerging NBAS genotype-phenotype correlations. Our findings highlight the power of a genome-first approach for an early diagnosis of complex phenotypes.

关键词： Intrauterine growth restriction NBAS CUL4B Osteogenesis imperfecta Bone Whole exome sequencing

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Accurate prediction of drug-induced heterogeneous response of red cell in vivo using a gravity-driven flow cytometry based on a microfluidic chip

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ANALYTICA CHIMICA ACTA 2022年 1221卷 340151页

作者： Chen, Yue Zhan, Qiong Zhang, Jian Wang, Wei Khoo, Bee Luan Liu, Zhen Wei, Siqi Niu, Junxin Xu, Jun Yu, Chia-Chen Hu, Xiumei Liu, Yanhui Han, Jongyoon Liu, Shuwen Liu, Lihong Southern Med Univ Sch Pharmaceut Sci NMPA Key Lab Res & Evaluat Drug Metab Guangdong Prov Key Lab New Drug Screening Guangzhou 510515 Peoples R China Southern Med Univ Nanfang Hosp Dept Cardiol Guangzhou 510515 Peoples R China Southern Med Univ Sch Basic Med Sci Dept Med Genet Guangzhou 510515 Peoples R China Hong Kong Ctr Cerebro Cardiovasc Hlth Engn Hong Kong Peoples R China City Univ Hong Kong Dept Biomed Engn Hong Kong Peoples R China City Univ Hong Kong Shenzhen Futian Res Inst Dept Precis Diagnost & Therapeut Technol Shenzhen 518057 Peoples R China MIT Dept Elect Engn & Comp Sci 77 Massachusetts Ave Cambridge MA 02139 USA Southern Med Univ Nanfang Hosp Dept Lab Med Guangzhou 510515 Peoples R China Jinzhou Peoples Hosp Internal Med Ward 1 Chaoyang St Jinzhou 052260 Peoples R China MIT Dept Biol Engn 77 Massachusetts Ave Cambridge MA 02139 USA Singapore MIT Alliance Res & Technol SMART Ctr Crit Analyt Mfg Personalized Med CAMP IRG & Antimicrobial Resistance AMR IRG Singapore 117543 Singapore

The drug-induced diverse response among patients is a severe problem for improving hemorheological character. However, there is no validated method for personalized therapy to the best of our knowledge. Here, we apply a gravity-driven deformability cytometry platform (GD-DCP) to profile the drug response of the red cell deform -ability (RCD) at the single-cell level using pentoxifylline (PTX) as a model drug, the effect of different concen-trations of PTX (0, 2, 20, 200 mu g mL(-1), the clinical dosage of PTX is 20 mu g mL(-1)) on RCD in patients with cardiovascular disease was explored. Based on the GD-DCP, about 38 and 56% of the acute phase of acute myocardial infarction (AMI) patients in the acute phase and coronary heart disease (CHD) patients respond positively to PTX, respectively, indicating that PTX has a strong patient dependency on RCD. Moreover, RCD is observed to be significantly inversely correlated with the activation of membrane protein kinase C (PKC) as well as the concentration of Ca2+ (both P < 0.001). The results of animal experiments show that the protective effects of PTX on myocardial ischemia rats have substantial individual variation, too. It is noted that the effect of PTX is highly consistent between RCD in vitro and in vivo outcomes (blood viscosity, myocardial injury, and electro-cardiogram (ECG)) in the same rat. All these new findings suggest that the GD-DCP is a promising method that uses deformability in vitro as one of the important criteria in personalized medicine, and our study provides unique insight into the individual-dependent mechanisms of PTX for improving RCD.

关键词： Personalized therapy Gravity -driven deformability cytometry platform Red cell deformability

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Mutations in KEOPS-complex genes cause nephrotic syndrome with primary microcephaly

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NATURE genetICS 2017年第10期49卷 1529-+页

作者： Braun, Daniela A. Rao, Jia Mollet, Geraldine Schapiro, David Daugeron, Marie-Claire Tan, Weizhen Gribouval, Olivier Boyer, Olivia Revy, Patrick Jobst-Schwan, Tilman Schmidt, Johanna Magdalena Lawson, Jennifer A. Schanze, Denny Ashraf, Shazia Ullmann, Jeremy F. P. Hoogstraten, Charlotte A. Boddaert, Nathalie Collinet, Bruno Martin, Gaelle Liger, Dominique Lovric, Svjetlana Furlano, Monica Guerrera, I. Chiara Sanchez-Ferras, Oraly Hu, Jennifer F. Boschat, Anne-Claire Sanquer, Sylvia Menten, Bjorn Vergult, Sarah De Rocker, Nina Airik, Merlin Hermle, Tobias Shril, Shirlee Widmeier, Eugen Gee, Heon Yung Choi, Won-Il Sadowski, Carolin E. Pabst, Werner L. Warejko, Jillian K. Daga, Ankana Basta, Tamara Matejas, Verena Scharmann, Karin Kienast, Sandra D. Behnam, Babak Beeson, Brendan Begtrup, Amber Bruce, Malcolm Ch'ng, Gaik-Siew Lin, Shuan-Pei Chang, Jui-Hsing Chen, Chao-Huei Cho, Megan T. Gaffney, Patrick M. Gipson, Patrick E. Hsu, Chyong-Hsin Kari, Jameela A. Ke, Yu-Yuan Kiraly-Borri, Cathy Lai, Wai-ming Lemyre, Emmanuelle Littlejohn, Rebecca Okashah Masri, Amira Moghtaderi, Mastaneh Nakamura, Kazuyuki Ozaltin, Fatih Praet, Marleen Prasad, Chitra Prytula, Agnieszka Roeder, Elizabeth R. Rump, Patrick Schnur, Rhonda E. Shiihara, Takashi Sinha, Manish D. Soliman, Neveen A. Soulami, Kenza Sweetser, David A. Tsai, Wen-Hui Tsai, Jeng-Daw Topaloglu, Rezan Vester, Udo Viskochil, David H. Vatanavicharn, Nithiwat Waxler, Jessica L. Wierenga, Klaas J. Wolf, Matthias T. F. Wong, Sik-Nin Leidel, Sebastian A. Truglio, Gessica Dedon, Peter C. Poduri, Annapurna Mane, Shrikant Lifton, Richard P. Bouchard, Maxime Kannu, Peter Chitayat, David Magen, Daniella Callewaert, Bert van Tilbeurgh, Herman Zenker, Martin Antignac, Corinne Hildebrandt, Friedhelm Boston Childrens Hosp Harvard Med Sch Boston MA USA INSERM Imagine Inst Lab Hereditary Kidney Dis UMR1163 Paris France Univ Paris 05 Sorbonne Paris Cite Imagine Inst Paris France Univ Paris Sud Univ Paris Saclay CNRS CEAInst Integrat Biol Cell I2BC Gif Sur Yvette France Hop Necker Enfants Malad AP HP Dept Pediat Nephrol Paris France INSERM U1163 Imagine Inst Lab Genome Dynam Immune Syst Paris France Univ Hosp Magdeburg Inst Human Genet Magdeburg Germany Boston Childrens Hosp Dept Neurol Epilepsy Genet Program Boston MA USA Boston Childrens Hosp Dept Neurol FM Kirby Neurobiol Ctr Boston MA USA Harvard Med Sch Dept Neurol Boston MA USA INSERM U1163 Imagine Inst Lab Mol & Pathophysiol Bases Cognit Disorders Paris France INSERM U1000 Paris France Hop Necker Enfants Malad AP HP Dept Pediat Radiol Paris France Sorbonne Univ UPMC UFR 927 Sci Vie Paris France Univ Paris 06 Sorbonne Univ Inst Mineral Phys Mat & Cosmochim UPMCUMR 7590 Paris France Univ Autonoma Barcelona Nephrol Dept Fundacio Puigvert IIB St Pau Barcelona Spain REDINREN Barcelona Spain Univ Paris 05 Struct Fedarat Rech Necker INSERM US24 CNRS UMS3633Proteom Platform 3P5 Necker Paris France McGill Univ Goodman Canc Res Ctr Montreal PQ Canada McGill Univ Dept Biochem Montreal PQ Canada MIT Dept Chem Cambridge MA 02139 USA MIT Dept Biol Engn 77 Massachusetts Ave Cambridge MA 02139 USA Imagine Inst Mass Spectrometry Platform Paris France Hop Necker Enfants Malad AP HP Dept Metabol & Prote Biochem Paris France Paris Descartes Sorbonne Paris Cite Univ INSERM UMR S1124 Paris France Ghent Univ Hosp Ctr Med Genet Ghent Belgium Univ Freiburg Dept Med Div Renal Fac MedMed Ctr Freiburg Germany Yonsei Univ Coll Med Dept Pharmacol Brain Korea PLUS Project Med Sci 21 Seoul South Korea Friedrich Alexander Univ Erlangen Nurnberg Inst Human Genet Erlangen Germany Max Planck Inst Mol Biomed Munster Germany Univ Munster Cells in Motion Cluster Excellence

Galloway-Mowat syndrome (GAMOS) is an autosomal-recessive disease characterized by the combination of early-onset nephrotic syndrome (SRNS) and microcephaly with brain anomalies. Here we identified recessive mutations in OSGEP, TP53RK, TPRKB, and LAGE3, genes encoding the four subunits of the KEOPS complex, in 37 individuals from 32 families with GAMOS. CRISPR-Cas9 knockout in zebrafish and mice recapitulated the human phenotype of primary microcephaly and resulted in early lethality. Knockdown of OSGEP, TP53RK, or TPRKB inhibited cell proliferation, which human mutations did not rescue. Furthermore, knockdown of these genes impaired protein translation, caused endoplasmic reticulum stress, activated DNA-damage-response signaling, and ultimately induced apoptosis. Knockdown of OSGEP or TP53RK induced defects in the actin cytoskeleton and decreased the migration rate of human podocytes, an established intermediate phenotype of SRNS. We thus identified four new monogenic causes of GAMOS, describe a link between KEOPS function and human disease, and delineate potential pathogenic mechanisms.

关键词： Focal segmental glomerulosclerosis genetics research Neurodevelopmental disorders

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