EGAGenomicsRNASeqhttps://ega-archive.org/studies/EGAS00001006339EGAEGA study EGAS00001006339Platelet RNAseq data for SLFN14 K219N patientsEGArestrictedbiochemical pathways, protein translation, Ribonucleic, Striadyne, 2610315D21Rik, Materials, determination, Adenosine Triphosphate, Laboratory, Blood, FKBP12-rapamycin complex-associated protein, Gene Expression Profile, ribosomal RNA, Ribosomal Protein, protein, Profiles, l(2)k03905, thrombocyte aggregation, DmTOR, 10, megalocaryocyte, dmTAF[[II]]230, 14, 17, Thrombocytes, diseases, responsivity, 23S, diseases and disorders, 3, RAFT1, Mammalian target of rapamycin, protein aggregate, Non Polyadenylated, RNA Gene Products, multicellular organismal biosynthetic process, 21, 23, 24, increased, 24E, Ribosomal, single-organism biosynthetic process, 26, Chromium Adenosine Triphosphate, human disease, 29, Gene Expressions, TFIID TAF250, cel, catabolism, Thrombocytopenias, 12S, "thrombocytopenia" EXACT [CSP2005:0446-5652], Bodily, Estimated, Signatures, dtor, high grade, "thrombocytopenia" EXACT [MTH:U000208], ATPsyn b, Secretion, 20-pentone, hereditary thrombocytopenia, anucleate thrombocyte, (1R, CrATP, Expression Signature, Cr(H2O)4 ATP, Secretions, Transcriptomes, biotransformation, Homo sapiens disease, transcription from bacterial-type RNA polymerase promoter, ATP, dTOR, dTor, Endoplasmic reticulum-to-nucleus signaling 1, Chromium Ammonium Salt, FK506-binding protein 12-rapamycin complex-associated protein 1, single organism signaling, Endoplasmic reticulum-to-nucleus signaling 2, 3R, rapamycin, "Thrombocytopenia, megakaryocytic cell line, ATPsyn-&bgr, 26E, Mechanistic target of rapamycin, protein anabolism, dTAF[[II]]230, protein biosynthetic process, ATPsyn-b, Megakaryocyte, PLATEST, aberrant, ribose nucleic acid, external secretion, Expression Profiles, ribonucleic acids, Blood Platelet, TAF200, TAFII-250, TAF250/230, Ire1-alpha, (-)-Rapamycin, exocrine gland fluid/secretion, Gene Expression, Bodily Secretion, TAFII250, ATP synthase D chain, "thrombocytopenia" EXACT [NCI2004_11_17:C3408], Ribonukleinsaeure, Expression Signatures, 15R, Manganese Salt, Diseases, protein formation, Magnesium Salt, pentosenucleic acids, Genetic Materials, secretion, Ribonucleic acids, laboratory, Expression Profile, 30-dimethoxy-15, Genetic Material, RAPT1, CG11154, Transcriptome Profiles, 28E, 16E, Acid, Mitochondrial, ribosomal protein, 4R)-4-hydroxy-3-methoxycyclohexyl]propan-2-yl}-19, Rapamycin and FKBP12 target 1, megacaryocyte, CG17603, TAF[[II]], CaATP, Phenotypes, disease, Slfn14-ps, Patient, protein synthesis, Taf250, Material, SR3-5, rRNA degradation, bacterial transcription, 5092, 36-dioxa-4-azatricyclo[30.3.1.0(4, MgATP, Platelet, blood platelet, Cistron, "Thrombocytopenia NOS (disorder)" EXACT [SNOMEDCT_2005_07_31:191326009], platelet, exocrine gland secretion, megalokaryocyte, Platelets, TAF230, accessory, bleeding, other disease, atypia, d230, Antibiotic AY 22989, Magnesium Adenosine Triphosphate, exocrine gland fluid, exocrine gland fluid or secretion, Transcriptome Profile, 18R, 35-hexamethyl-11, CG5092, Thrombopenias, ATP-MgCl2, Gene, dTAFII250, rRNA breakdown, IB, protein-containing complex, Hemorrhages, mitochondrial, EfW1, supernumerary, l(2)k17004, Adenylpyrophosphate, dmTAF1, 19R, Taf230, ATP-synbeta, Gene Products, thrombocyte, 18-dihydroxy-12-{(2S)-1-[(1S, disease or disorder, atypical, TOR, 9S, TAF250, DmelCG8274, mIre1, study, reactivity, Taf200, dTAF[[II]]250, Genetic, Bx34, DmelCG11154, 35R)-1, "Thrombocytopenia (disorder)" EXACT [SNOMEDCT_2005_07_31:70786006], cell, AY 22-989, Profile, 9)]hexatriaconta-16, Aggregation, beta-ATPase, ATP MgCl2, Taf1p, Low platelet count, flat, tor, Tpr, TPR, Expressions, rRNA catabolism, Non-Polyadenylated RNA, non-neoplastic, dTAF250, secreted substance, Chromium Salt, ATPasebeta, bodily secretion, MnATP, ATPase beta, Clients, disorder, Expression, TAF, AY 22989, Thrombocyte, Frap1, CT24817, ATPB, RNA, TAF[[II]]250, Transcriptome, degradation, protein complex, "Thrombocytopenia NOS" EXACT [SNOMEDCT_2005_07_31:154827000]., hIRE1p, Proteins, AY 22 989, disorders, Magnesium Chloride, l(3)84Ab, RNS, FRAP1, 30S, function, medical condition, BG:DS00004.13, defective, FRAP2, mTOR, FRAP/TOR, Adenosine 5'-(tetrahydrogen triphosphate), Cistrons, DmelCG5092, Client, Cell, dTAF230, ATP-syn-B, 2.7.11.1, Atriphos, IRE1b, IRE1a, ML-1, native protein, Rapamycin, I2190A, yeast nucleic acid, Serine|threonine-protein kinase, Ire1-beta, p230, Protein, Gene Expression Signatures, chemical analysis, I-2190A, sirolimusum, TAF[[II]]250/230, Inositol-requiring protein 1, condition, protein biosynthesis, TFIID, Inositol-requiring protein 2, Gene Expression Signature, "Platelet count below reference range" EXACT [SNOMEDCT_2005_07_31:415116008], Taf[[II]]250, "Thrombocytopenic disorder (disorder)" EXACT [SNOMEDCT_2005_07_31:302215000], ribonucleic acid, unspecified" EXACT [ICD9CM_2006:287.5], Manganese Adenosine Triphosphate, TAF[[II]]230, biodegradation, 3.1.26.-, increased number, I 2190A, Non Polyadenylated RNA, Bleeding, Thrombopenia, Non-Polyadenylated, 28-tetraene-2, CT24745, 32S, Rapamycin target protein 1, TAF[II]250, AI327068, Ribonucleic Acid, sirolimus, enucleate thrombocyte, FRAP, Rapamune, Protein Gene Products, Gene Proteins, present in greater numbers in organism, Gm20, DmelCG17603, CT16317, signalling process, haemorrhage, Gene Expression Profiles, CG8274, ATPIB, MTOR, hIRE2p, 21R, assay, response, Signature, Calcium Salt, Endoribonuclease, TAF1Gm20, Slfn14-ps, Client., Thrombocytes, anucleate thrombocyte, Patient, Clients, Blood, thrombocyte, Blood Platelet, blood platelet, Platelet, enucleate thrombocyte, platelet, Thrombocyte, PlateletsfalsePlatelet RNAseq data for SLFN14 K219N patientsPathogenic missense variants in SLFN14, which encodes an RNA endoribonuclease protein that regulates rRNA degradation, are known to cause inherited thrombocytopenia with impaired platelet aggregation and ATP secretion. Despite rather mild laboratory defects, these patients display an obvious bleeding phenotype. The function of SLFN14 in megakaryocyte (MK) and platelet biology is unknown. This study aims to characterize the platelet transcriptome in patients with a SLFN14 K219N variant and model the disease in the immortalized megakaryocyte cell line imMKCL. Total platelet RNA was sequenced for two patients and 19 healthy controls. Differential gene expression analysis yielded a total of 2999 and 2888 significantly (|log2FC|>1, FDR<0.05) up- and downregulated genes, respectively. Remarkably, these downregulated genes were not enriched for any biological pathway while upregulated genes were enriched for pathways involved in (mitochondrial) translation and transcription with a significant upregulation of 134 ribosomal protein genes (RPG). Heterozygous and homozygous SLFN14 K219N imMKCL showed a defect in MK differentiation that aggravated during cell passaging of undifferentiated cells and in proplatelet formation. SLFN14 defective platelets and MK showed signs of rRNA degradation while this was absent in undifferentiated imMKCL cells. Upregulation of RPG through increased mTOR signaling in SLFN14 K219N MK seems to be a compensatory response for rRNA degradation. Indeed, mTOR inhibition with rapamycin resulted in further enhanced rRNA degradation in SLFN14 K219N MK. Taken together, our study indicates dysregulation of mTOR-regulated ribosomal biogenesis as the disease mechanism for SLFN14-related thrombocytopenia.2023-02-06 12:04:51EGAS000010063399606EGAD00001008965EGAC00001002725