{"gene":"HNRNPH2","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":2007,"finding":"hnRNPH2 (together with hnRNPF) binds G-rich enhancer sequences in exon 3B of PLP/DM20 pre-mRNA and promotes DM20 5' splice site selection in oligodendrocytes; knockdown of hnRNPH increased the PLP/DM20 ratio, while simultaneous knockdown of hnRNPH and hnRNPF showed a synergistic increase, dependent on the G-rich M2 enhancer.","method":"siRNA knockdown of hnRNPH and/or hnRNPF in differentiated oligodendrocytes, minigene splicing assays, mutational analysis of G-rich sequences, protein-RNA binding assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — multiple orthogonal methods (siRNA KD, minigene, mutagenesis, binding assays) in a single study with clear functional readout","pmids":["17567613"],"is_preprint":false},{"year":2011,"finding":"hnRNPH controls oncogenic splicing switches in glioblastoma: it promotes production of the anti-apoptotic MADD isoform (by regulating IG20/MADD exon 16 inclusion) and a ligand-independent constitutively active RON tyrosine kinase variant (by regulating RON exon 11 skipping), thereby promoting cell survival and invasion. Ablation of hnRNPH caused increased cell death and reduced invasiveness that could be rescued by isoform-specific knockdown of the respective variants.","method":"siRNA knockdown of hnRNPH in GBM cells, isoform-specific knockdown/splicing redirection with antisense oligonucleotides, cell death and invasion assays, epistasis rescue experiments","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal rescue epistasis with multiple orthogonal knockdown approaches and functional cellular readouts; replicated across two splicing targets","pmids":["21915099"],"is_preprint":false},{"year":2014,"finding":"hnRNPH binds G-containing sequences at an intronic SNP site (rs9479757) in OPRM1 pre-mRNA, as demonstrated by EMSA; this binding regulates alternative splicing of OPRM1 exon 2. The G-to-A SNP transition weakens hnRNPH binding, promotes exon 2 skipping, and alters OPRM1 splice-variant mRNA and hMOR-1 protein levels.","method":"Electrophoretic mobility shift assay (EMSA), minigene splicing assay, siRNA knockdown, antisense morpholino oligonucleotides, human postmortem brain tissue analysis","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — EMSA binding assay plus minigene and siRNA functional validation with multiple orthogonal methods in one study","pmids":["25122903"],"is_preprint":false},{"year":2016,"finding":"De novo missense variants in HNRNPH2 cluster within its nuclear localization signal (NLS), disrupting normal nuclear localization and causing cytoplasmic accumulation of the protein, leading to a neurodevelopmental disorder in females.","method":"Whole-exome sequencing identifying NLS variants; functional inference from variant location within the NLS domain","journal":"American journal of human genetics","confidence":"Low","confidence_rationale":"Tier 4 / Weak — variant identification by sequencing; no direct localization experiment reported in this abstract","pmids":["27545675"],"is_preprint":false},{"year":2021,"finding":"Pathogenic HNRNPH2 missense variants p.(Arg206Gln) and p.(Pro209Leu) located within the NLS cause dysfunctional nucleocytoplasmic shuttling (cytoplasmic accumulation) of the protein, whereas the p.(Arg114Trp) variant (within the second qRRM) shows reduced interaction with members of the large assembly of splicing regulators (LASR). The p.(Arg114Trp) variant also causes substantial alterations in alternative splicing regulation and global transcriptome changes in patient fibroblasts.","method":"Functional in vitro characterization of NLS variants (nucleocytoplasmic shuttling assays), co-immunoprecipitation for LASR interaction, RNA-sequencing of patient fibroblasts","journal":"Human genetics","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — multiple functional assays (shuttling, Co-IP, RNA-seq) in a single lab; methods described at abstract level without full mechanistic detail","pmids":["34907471"],"is_preprint":false},{"year":2021,"finding":"PRMT1-dependent arginine methylation of hnRNP H (hepatic) suppresses its binding to complement component C3 mRNA and other complement pathway mRNAs, thereby reducing complement component expression. Phosphorylation is required for this PRMT1-dependent function.","method":"Mass spectrometry of PRMT1-dependent arginine methylated proteome in mouse liver, in vitro binding assays, hepatocyte-specific PRMT1 knockout mice with complement expression and serum complement activation readouts","journal":"Hepatology communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS identification plus functional KO mouse model; study focuses on hnRNPH1 in mouse liver rather than HNRNPH2 specifically; inclusion is uncertain but reported as hnRNP H","pmids":["34027271"],"is_preprint":false},{"year":2023,"finding":"NLS mutations in hnRNPH2 reduce its interaction with the nuclear transport receptor Karyopherin-β2 (Kapβ2/Transportin-1), resulting in modest cytoplasmic accumulation of hnRNPH2. Knockin mice with human-equivalent NLS mutations recapitulate clinical features including impaired motor/cognitive function and audiogenic seizures, while Hnrnph2-KO mice show no detectable phenotype due to compensatory upregulation of the paralog Hnrnph1. Knockin mice fail to upregulate Hnrnph1, suggesting that the disorder involves either toxic gain of function or complex loss of function with impaired paralog compensation.","method":"Knockin and knockout mouse models, co-immunoprecipitation for Kapβ2 interaction, behavioral/seizure phenotyping, Hnrnph1 expression analysis","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — two independent KI lines and KO mice with multiple phenotypic readouts plus Co-IP interaction data; replicated across two knockin models","pmids":["37463454"],"is_preprint":false},{"year":2023,"finding":"Crystal/structural analysis of the Karyopherin-β2•HNRNPH2 complex revealed that Karyopherin-β2 binds HNRNPH2 residues 204–215, comprising a PY-NLS with an R-X2-4-P-Y motif (206RPGPY210) followed by a new binding epitope (211DRP213) that contacts Karyopherin-β2 W373. Mutations at each site decrease Karyopherin-β2 binding affinity 70–100 fold, explaining cytoplasmic accumulation of disease-associated variants.","method":"Structure determination of Karyopherin-β2•HNRNPH2 complex, site-directed mutagenesis, binding affinity measurements","journal":"bioRxiv (preprint)","confidence":"High","confidence_rationale":"Tier 1 / Moderate — structural determination combined with mutagenesis and quantitative binding measurements; single lab preprint","pmids":["36711837"],"is_preprint":true},{"year":2020,"finding":"Chicken hnRNPH2 interacts with the N-terminal CARD-containing domain of chicken MDA5 (chMDA5-N) and impairs the association between chMDA5-N and its downstream adaptor MAVS, thereby acting as a negative regulator of the chMDA5-mediated type I interferon signaling pathway.","method":"Pulldown assay, mass spectrometry, cloning and expression of 64 chicken genes, co-immunoprecipitation for chMDA5-N/MAVS interaction, IFN-β reporter assay","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — pulldown/MS identification confirmed by Co-IP and functional IFN-β reporter assay; chicken ortholog, single lab","pmids":["33123126"],"is_preprint":false},{"year":2025,"finding":"HNRNPH2 modulates alternative splicing of HNRNPH1 pre-mRNA to regulate HNRNPH1 expression levels. ASO-mediated knockdown of Hnrnph2 induces compensatory upregulation of Hnrnph1 through this splicing-based mechanism and rescues audiogenic seizures, motor, and cognitive phenotypes in mutant Hnrnph2 knockin mice.","method":"Antisense oligonucleotide (ASO) knockdown in vivo (intracerebroventricular injection), RT-PCR/RNA-seq for alternative splicing analysis, behavioral and seizure phenotyping, human iPSC-derived neurons","journal":"Science translational medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo mouse model rescue with multiple phenotypic readouts plus iPSC-derived neuron validation; mechanistic splicing link established across model systems","pmids":["42018666"],"is_preprint":false},{"year":2025,"finding":"The HNRNPH2 P213L mutation (p.Pro213Leu) disrupts the interaction between hnRNPH2 and its target mRNA transcripts related to myelination, leading to downregulation of myelin-related genes and impaired oligodendrocyte progenitor cell differentiation, resulting in myelination defects and spatial learning deficits in knockin mice.","method":"Knockin mouse model (Hnrnph2P213L), RNA-IP or equivalent binding assay for interaction with target transcripts, gene expression analysis, oligodendrocyte differentiation assays, benztropine rescue experiment, behavioral testing","journal":"Journal of genetics and genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockin mouse model with cellular (oligodendrocyte differentiation) and molecular (target mRNA binding) readouts; single lab study","pmids":["41443536"],"is_preprint":false},{"year":2026,"finding":"RNA G-quadruplexes (rG4s) mediate cooperative binding of HNRNPH to RNA: HNRNPH unfolds rG4 structures to expose multiple G-rich binding sites, establishing indirect cooperativity that produces switch-like regulation of hundreds of alternative splicing events. This cooperative mechanism was characterized by in vivo and in vitro binding studies combined with theoretical modeling.","method":"High-throughput in vivo and in vitro RNA binding studies (including CLIP-based approaches), rG4-unfolding assays, theoretical cooperativity modeling, splicing analysis in cells and breast cancer patient data","journal":"bioRxiv (preprint)","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — multiple orthogonal in vivo/in vitro methods with modeling; preprint, single lab, study covers HNRNPH broadly and likely applies to HNRNPH2 as well as HNRNPH1","pmids":["41867855"],"is_preprint":true}],"current_model":"HNRNPH2 is a nuclear RNA-binding protein that imports into the nucleus via a PY-NLS recognized by Karyopherin-β2/Transportin-1; once nuclear, it binds G-rich sequences and RNA G-quadruplexes in pre-mRNA to regulate alternative splicing of hundreds of targets (including oncogenic splicing switches, myelin protein transcripts, and opioid receptor variants) through cooperative, switch-like mechanisms, and its expression level is itself regulated by alternative splicing feedback involving its paralog HNRNPH1; disease-associated NLS missense mutations disrupt Karyopherin-β2 binding and cause cytoplasmic accumulation with consequent splicing dysregulation and neurodevelopmental disorder, while qRRM mutations impair interaction with the LASR splicing complex."},"narrative":{"mechanistic_narrative":"HNRNPH2 is a nuclear RNA-binding protein that regulates alternative splicing of pre-mRNA by binding G-rich sequences and RNA G-quadruplexes, governing developmentally and oncogenically important splicing decisions [PMID:17567613, PMID:25122903, PMID:41867855]. It recognizes G-rich enhancer elements—exemplified by the M2 enhancer of PLP/DM20 pre-mRNA in oligodendrocytes—and operates with its paralog hnRNPF to direct splice-site selection [PMID:17567613]; mechanistically, it unfolds RNA G-quadruplexes to expose clustered G-rich sites, producing indirect cooperativity and switch-like control over hundreds of splicing events [PMID:41867855]. Through such switches it drives oncogenic splice variants in glioblastoma, promoting the anti-apoptotic MADD isoform and a constitutively active RON kinase variant to support survival and invasion [PMID:21915099], and it shapes OPRM1 exon 2 inclusion at a G-containing intronic site [PMID:25122903]. Nuclear import depends on a PY-NLS (residues 204–215, bearing an R-X2-4-P-Y motif and an adjacent DRP epitope) recognized by Karyopherin-β2/Transportin-1 [PMID:36711837]. De novo missense variants clustering in this NLS reduce Karyopherin-β2 binding and cause cytoplasmic accumulation, defining a neurodevelopmental disorder; knock-in mice recapitulate motor, cognitive, and audiogenic-seizure phenotypes [PMID:27545675, PMID:37463454, PMID:36711837]. HNRNPH2 expression is coupled to its paralog through splicing feedback: it modulates HNRNPH1 pre-mRNA splicing, and antisense-mediated Hnrnph2 knockdown drives compensatory Hnrnph1 upregulation that rescues disease phenotypes in mutant mice [PMID:42018666]. Additional disease alleles act through distinct routes—the qRRM variant p.Arg114Trp impairs interaction with the LASR splicing complex [PMID:34907471], and the P213L variant disrupts binding to myelin-related transcripts, impairing oligodendrocyte differentiation and myelination [PMID:41443536].","teleology":[{"year":2007,"claim":"Established that hnRNPH2 is a sequence-specific splicing regulator that recognizes G-rich enhancers and selects splice sites, working synergistically with hnRNPF.","evidence":"siRNA knockdown, minigene splicing assays, and G-rich mutagenesis in differentiated oligodendrocytes (PLP/DM20)","pmids":["17567613"],"confidence":"High","gaps":["Did not define structural basis of G-rich recognition","HNRNPH2-specific versus hnRNPH family contributions not separated"]},{"year":2011,"claim":"Connected hnRNPH-controlled splicing switches to cancer cell phenotypes, showing causal roles in survival and invasion via specific oncogenic isoforms.","evidence":"siRNA knockdown plus isoform-specific ASO rescue/epistasis in glioblastoma cells with death and invasion readouts","pmids":["21915099"],"confidence":"High","gaps":["Did not distinguish HNRNPH1 from HNRNPH2 contributions","No structural or binding-site map of the regulated exons"]},{"year":2014,"claim":"Demonstrated direct G-containing sequence binding controls a clinically relevant splice variant and that a single SNP can tune hnRNPH-dependent splicing output.","evidence":"EMSA, minigene assays, siRNA/morpholino knockdown, and human postmortem brain analysis at OPRM1 rs9479757","pmids":["25122903"],"confidence":"High","gaps":["In vivo physiological consequence of altered hMOR-1 levels not established","Did not resolve paralog-specific binding"]},{"year":2016,"claim":"Linked HNRNPH2 NLS variants to a human neurodevelopmental disorder, implicating disrupted nuclear localization.","evidence":"Whole-exome sequencing identifying NLS-clustered de novo variants with functional inference","pmids":["27545675"],"confidence":"Low","gaps":["No direct localization experiment reported in this study","Causality of mislocalization for phenotype not demonstrated"]},{"year":2021,"claim":"Distinguished two mutational mechanisms—NLS variants impairing shuttling versus a qRRM variant impairing splicing-complex interaction.","evidence":"Nucleocytoplasmic shuttling assays, Co-IP for LASR interaction, and RNA-seq of patient fibroblasts","pmids":["34907471"],"confidence":"Medium","gaps":["LASR interaction shown by Co-IP without structural detail","Causal chain from transcriptome changes to disease unresolved"]},{"year":2023,"claim":"Identified Karyopherin-β2 as the import receptor and resolved the PY-NLS structural determinants quantitatively explaining variant mislocalization.","evidence":"Structure of Kapβ2•HNRNPH2 complex with site-directed mutagenesis and binding-affinity measurements (preprint)","pmids":["36711837"],"confidence":"High","gaps":["Preprint, single lab","Did not test impact on downstream splicing in cells"]},{"year":2023,"claim":"Showed in vivo that NLS mutations reduce Kapβ2 binding and recapitulate disease phenotypes, and revealed paralog compensation buffering loss of function.","evidence":"Two knock-in lines and KO mice, Co-IP for Kapβ2, behavioral/seizure phenotyping, and Hnrnph1 expression analysis","pmids":["37463454"],"confidence":"High","gaps":["Did not resolve toxic gain-of-function versus loss-of-function definitively","Mechanism of failed Hnrnph1 upregulation in knock-ins unclear"]},{"year":2025,"claim":"Defined the splicing-based feedback by which HNRNPH2 controls HNRNPH1 levels and exploited it therapeutically via ASO-driven paralog compensation.","evidence":"In vivo ASO knockdown (ICV), RNA-seq/RT-PCR splicing analysis, behavioral rescue, and iPSC-derived neuron validation","pmids":["42018666"],"confidence":"High","gaps":["Long-term durability and safety of ASO rescue not established","Full set of co-regulated splicing targets not mapped"]},{"year":2025,"claim":"Tied a specific patient mutation to a myelination program, linking impaired target-mRNA binding to oligodendrocyte differentiation defects.","evidence":"Hnrnph2P213L knock-in mice, RNA-IP/binding assays, oligodendrocyte differentiation assays, benztropine rescue, and behavioral testing","pmids":["41443536"],"confidence":"Medium","gaps":["Single-lab study","Direct target transcripts incompletely catalogued"]},{"year":2026,"claim":"Provided a biophysical mechanism—rG4 unfolding generating cooperative multi-site binding—for switch-like control of large splicing programs.","evidence":"In vivo/in vitro CLIP-based binding, rG4-unfolding assays, cooperativity modeling, and splicing analysis with patient data (preprint)","pmids":["41867855"],"confidence":"Medium","gaps":["Preprint, single lab","Study covers HNRNPH broadly; HNRNPH2-specific cooperativity not isolated"]},{"year":null,"claim":"How HNRNPH2's splicing functions, paralog feedback, and post-translational regulation integrate to produce the disorder—and whether the mechanism is gain- or loss-of-function—remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["Gain- versus loss-of-function not definitively settled","Cell-type-specific splicing target maps incomplete","Post-translational regulation of HNRNPH2 in humans uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,2,11]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,1,11]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[3,6,7]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[4,6]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,1,11]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[6,7]}],"complexes":[],"partners":["HNRNPF","TNPO1","HNRNPH1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P55795","full_name":"Heterogeneous nuclear ribonucleoprotein H2","aliases":["FTP-3","Heterogeneous nuclear ribonucleoprotein H'","hnRNP H'"],"length_aa":449,"mass_kda":49.3,"function":"This protein is a component of the heterogeneous nuclear ribonucleoprotein (hnRNP) complexes which provide the substrate for the processing events that pre-mRNAs undergo before becoming functional, translatable mRNAs in the cytoplasm. Binds poly(RG)","subcellular_location":"Nucleus, nucleoplasm","url":"https://www.uniprot.org/uniprotkb/P55795/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/HNRNPH2","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CAPZB","stoichiometry":0.2},{"gene":"CLNS1A","stoichiometry":0.2},{"gene":"HNRNPH1","stoichiometry":0.2},{"gene":"INPP5E","stoichiometry":0.2},{"gene":"RBM14","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/HNRNPH2","total_profiled":1310},"omim":[{"mim_id":"620083","title":"NEURODEVELOPMENTAL DISORDER WITH CRANIOFACIAL DYSMORPHISM AND SKELETAL DEFECTS; NEDCDS","url":"https://www.omim.org/entry/620083"},{"mim_id":"602027","title":"TELOMERIC REPEAT-BINDING FACTOR 2; TERF2","url":"https://www.omim.org/entry/602027"},{"mim_id":"601035","title":"HETEROGENEOUS NUCLEAR RIBONUCLEOPROTEIN H1; HNRNPH1","url":"https://www.omim.org/entry/601035"},{"mim_id":"300986","title":"INTELLECTUAL DEVELOPMENTAL DISORDER, X-LINKED, SYNDROMIC, BAIN TYPE; MRXSB","url":"https://www.omim.org/entry/300986"},{"mim_id":"300610","title":"HETEROGENEOUS NUCLEAR RIBONUCLEOPROTEIN H2; HNRNPH2","url":"https://www.omim.org/entry/300610"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/HNRNPH2"},"hgnc":{"alias_symbol":["hnRNPH'","FTP3","HNRPH'"],"prev_symbol":["HNRPH2"]},"alphafold":{"accession":"P55795","domains":[{"cath_id":"3.30.70.330","chopping":"10-99","consensus_level":"high","plddt":80.3888,"start":10,"end":99},{"cath_id":"3.30.70.330","chopping":"111-194","consensus_level":"high","plddt":77.4049,"start":111,"end":194},{"cath_id":"3.30.70.330","chopping":"288-362","consensus_level":"high","plddt":80.5135,"start":288,"end":362}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P55795","model_url":"https://alphafold.ebi.ac.uk/files/AF-P55795-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P55795-F1-predicted_aligned_error_v6.png","plddt_mean":61.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=HNRNPH2","jax_strain_url":"https://www.jax.org/strain/search?query=HNRNPH2"},"sequence":{"accession":"P55795","fasta_url":"https://rest.uniprot.org/uniprotkb/P55795.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P55795/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P55795"}},"corpus_meta":[{"pmid":"21915099","id":"PMC_21915099","title":"Splicing factor hnRNPH drives an oncogenic splicing switch in gliomas.","date":"2011","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/21915099","citation_count":138,"is_preprint":false},{"pmid":"17567613","id":"PMC_17567613","title":"PLP/DM20 ratio is regulated by hnRNPH and F and a novel G-rich enhancer in oligodendrocytes.","date":"2007","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/17567613","citation_count":66,"is_preprint":false},{"pmid":"27545675","id":"PMC_27545675","title":"Variants in HNRNPH2 on the X Chromosome Are Associated with a Neurodevelopmental Disorder in Females.","date":"2016","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/27545675","citation_count":61,"is_preprint":false},{"pmid":"25122903","id":"PMC_25122903","title":"A heroin addiction severity-associated intronic single nucleotide polymorphism modulates alternative pre-mRNA splicing of the μ opioid receptor gene OPRM1 via hnRNPH interactions.","date":"2014","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/25122903","citation_count":49,"is_preprint":false},{"pmid":"31444317","id":"PMC_31444317","title":"LncRNA RP11-670E13.6, interacted with hnRNPH, delays cellular senescence by sponging microRNA-663a in UVB damaged dermal fibroblasts.","date":"2019","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/31444317","citation_count":22,"is_preprint":false},{"pmid":"34907471","id":"PMC_34907471","title":"Variant-specific effects define the phenotypic spectrum of HNRNPH2-associated neurodevelopmental disorders in males.","date":"2021","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/34907471","citation_count":21,"is_preprint":false},{"pmid":"31670473","id":"PMC_31670473","title":"Bain type of X-linked syndromic mental retardation in a male with a pathogenic variant in HNRNPH2.","date":"2019","source":"American journal of medical genetics. 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disorder","date":"2025-11-05","source":"bioRxiv","url":"https://doi.org/10.1101/2025.11.04.686541","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.08.21.24312358","title":"aiHumanoid Simulations Uncover Dominant-Negative Effects in HNRNPH2-Related Neurodevelopmental Disorders","date":"2024-08-21","source":"bioRxiv","url":"https://doi.org/10.1101/2024.08.21.24312358","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.03.04.641446","title":"Sex-biased Transcriptome in  <i>in vitro</i>  Produced Bovine Early Embryos","date":"2025-03-04","source":"bioRxiv","url":"https://doi.org/10.1101/2025.03.04.641446","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":14670,"output_tokens":3457,"usd":0.047933,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11135,"output_tokens":3391,"usd":0.070225,"stage2_stop_reason":"end_turn"},"total_usd":0.118158,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2007,\n      \"finding\": \"hnRNPH2 (together with hnRNPF) binds G-rich enhancer sequences in exon 3B of PLP/DM20 pre-mRNA and promotes DM20 5' splice site selection in oligodendrocytes; knockdown of hnRNPH increased the PLP/DM20 ratio, while simultaneous knockdown of hnRNPH and hnRNPF showed a synergistic increase, dependent on the G-rich M2 enhancer.\",\n      \"method\": \"siRNA knockdown of hnRNPH and/or hnRNPF in differentiated oligodendrocytes, minigene splicing assays, mutational analysis of G-rich sequences, protein-RNA binding assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — multiple orthogonal methods (siRNA KD, minigene, mutagenesis, binding assays) in a single study with clear functional readout\",\n      \"pmids\": [\"17567613\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"hnRNPH controls oncogenic splicing switches in glioblastoma: it promotes production of the anti-apoptotic MADD isoform (by regulating IG20/MADD exon 16 inclusion) and a ligand-independent constitutively active RON tyrosine kinase variant (by regulating RON exon 11 skipping), thereby promoting cell survival and invasion. Ablation of hnRNPH caused increased cell death and reduced invasiveness that could be rescued by isoform-specific knockdown of the respective variants.\",\n      \"method\": \"siRNA knockdown of hnRNPH in GBM cells, isoform-specific knockdown/splicing redirection with antisense oligonucleotides, cell death and invasion assays, epistasis rescue experiments\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal rescue epistasis with multiple orthogonal knockdown approaches and functional cellular readouts; replicated across two splicing targets\",\n      \"pmids\": [\"21915099\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"hnRNPH binds G-containing sequences at an intronic SNP site (rs9479757) in OPRM1 pre-mRNA, as demonstrated by EMSA; this binding regulates alternative splicing of OPRM1 exon 2. The G-to-A SNP transition weakens hnRNPH binding, promotes exon 2 skipping, and alters OPRM1 splice-variant mRNA and hMOR-1 protein levels.\",\n      \"method\": \"Electrophoretic mobility shift assay (EMSA), minigene splicing assay, siRNA knockdown, antisense morpholino oligonucleotides, human postmortem brain tissue analysis\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — EMSA binding assay plus minigene and siRNA functional validation with multiple orthogonal methods in one study\",\n      \"pmids\": [\"25122903\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"De novo missense variants in HNRNPH2 cluster within its nuclear localization signal (NLS), disrupting normal nuclear localization and causing cytoplasmic accumulation of the protein, leading to a neurodevelopmental disorder in females.\",\n      \"method\": \"Whole-exome sequencing identifying NLS variants; functional inference from variant location within the NLS domain\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — variant identification by sequencing; no direct localization experiment reported in this abstract\",\n      \"pmids\": [\"27545675\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Pathogenic HNRNPH2 missense variants p.(Arg206Gln) and p.(Pro209Leu) located within the NLS cause dysfunctional nucleocytoplasmic shuttling (cytoplasmic accumulation) of the protein, whereas the p.(Arg114Trp) variant (within the second qRRM) shows reduced interaction with members of the large assembly of splicing regulators (LASR). The p.(Arg114Trp) variant also causes substantial alterations in alternative splicing regulation and global transcriptome changes in patient fibroblasts.\",\n      \"method\": \"Functional in vitro characterization of NLS variants (nucleocytoplasmic shuttling assays), co-immunoprecipitation for LASR interaction, RNA-sequencing of patient fibroblasts\",\n      \"journal\": \"Human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — multiple functional assays (shuttling, Co-IP, RNA-seq) in a single lab; methods described at abstract level without full mechanistic detail\",\n      \"pmids\": [\"34907471\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PRMT1-dependent arginine methylation of hnRNP H (hepatic) suppresses its binding to complement component C3 mRNA and other complement pathway mRNAs, thereby reducing complement component expression. Phosphorylation is required for this PRMT1-dependent function.\",\n      \"method\": \"Mass spectrometry of PRMT1-dependent arginine methylated proteome in mouse liver, in vitro binding assays, hepatocyte-specific PRMT1 knockout mice with complement expression and serum complement activation readouts\",\n      \"journal\": \"Hepatology communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS identification plus functional KO mouse model; study focuses on hnRNPH1 in mouse liver rather than HNRNPH2 specifically; inclusion is uncertain but reported as hnRNP H\",\n      \"pmids\": [\"34027271\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"NLS mutations in hnRNPH2 reduce its interaction with the nuclear transport receptor Karyopherin-β2 (Kapβ2/Transportin-1), resulting in modest cytoplasmic accumulation of hnRNPH2. Knockin mice with human-equivalent NLS mutations recapitulate clinical features including impaired motor/cognitive function and audiogenic seizures, while Hnrnph2-KO mice show no detectable phenotype due to compensatory upregulation of the paralog Hnrnph1. Knockin mice fail to upregulate Hnrnph1, suggesting that the disorder involves either toxic gain of function or complex loss of function with impaired paralog compensation.\",\n      \"method\": \"Knockin and knockout mouse models, co-immunoprecipitation for Kapβ2 interaction, behavioral/seizure phenotyping, Hnrnph1 expression analysis\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — two independent KI lines and KO mice with multiple phenotypic readouts plus Co-IP interaction data; replicated across two knockin models\",\n      \"pmids\": [\"37463454\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Crystal/structural analysis of the Karyopherin-β2•HNRNPH2 complex revealed that Karyopherin-β2 binds HNRNPH2 residues 204–215, comprising a PY-NLS with an R-X2-4-P-Y motif (206RPGPY210) followed by a new binding epitope (211DRP213) that contacts Karyopherin-β2 W373. Mutations at each site decrease Karyopherin-β2 binding affinity 70–100 fold, explaining cytoplasmic accumulation of disease-associated variants.\",\n      \"method\": \"Structure determination of Karyopherin-β2•HNRNPH2 complex, site-directed mutagenesis, binding affinity measurements\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — structural determination combined with mutagenesis and quantitative binding measurements; single lab preprint\",\n      \"pmids\": [\"36711837\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Chicken hnRNPH2 interacts with the N-terminal CARD-containing domain of chicken MDA5 (chMDA5-N) and impairs the association between chMDA5-N and its downstream adaptor MAVS, thereby acting as a negative regulator of the chMDA5-mediated type I interferon signaling pathway.\",\n      \"method\": \"Pulldown assay, mass spectrometry, cloning and expression of 64 chicken genes, co-immunoprecipitation for chMDA5-N/MAVS interaction, IFN-β reporter assay\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — pulldown/MS identification confirmed by Co-IP and functional IFN-β reporter assay; chicken ortholog, single lab\",\n      \"pmids\": [\"33123126\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"HNRNPH2 modulates alternative splicing of HNRNPH1 pre-mRNA to regulate HNRNPH1 expression levels. ASO-mediated knockdown of Hnrnph2 induces compensatory upregulation of Hnrnph1 through this splicing-based mechanism and rescues audiogenic seizures, motor, and cognitive phenotypes in mutant Hnrnph2 knockin mice.\",\n      \"method\": \"Antisense oligonucleotide (ASO) knockdown in vivo (intracerebroventricular injection), RT-PCR/RNA-seq for alternative splicing analysis, behavioral and seizure phenotyping, human iPSC-derived neurons\",\n      \"journal\": \"Science translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo mouse model rescue with multiple phenotypic readouts plus iPSC-derived neuron validation; mechanistic splicing link established across model systems\",\n      \"pmids\": [\"42018666\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The HNRNPH2 P213L mutation (p.Pro213Leu) disrupts the interaction between hnRNPH2 and its target mRNA transcripts related to myelination, leading to downregulation of myelin-related genes and impaired oligodendrocyte progenitor cell differentiation, resulting in myelination defects and spatial learning deficits in knockin mice.\",\n      \"method\": \"Knockin mouse model (Hnrnph2P213L), RNA-IP or equivalent binding assay for interaction with target transcripts, gene expression analysis, oligodendrocyte differentiation assays, benztropine rescue experiment, behavioral testing\",\n      \"journal\": \"Journal of genetics and genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockin mouse model with cellular (oligodendrocyte differentiation) and molecular (target mRNA binding) readouts; single lab study\",\n      \"pmids\": [\"41443536\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"RNA G-quadruplexes (rG4s) mediate cooperative binding of HNRNPH to RNA: HNRNPH unfolds rG4 structures to expose multiple G-rich binding sites, establishing indirect cooperativity that produces switch-like regulation of hundreds of alternative splicing events. This cooperative mechanism was characterized by in vivo and in vitro binding studies combined with theoretical modeling.\",\n      \"method\": \"High-throughput in vivo and in vitro RNA binding studies (including CLIP-based approaches), rG4-unfolding assays, theoretical cooperativity modeling, splicing analysis in cells and breast cancer patient data\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — multiple orthogonal in vivo/in vitro methods with modeling; preprint, single lab, study covers HNRNPH broadly and likely applies to HNRNPH2 as well as HNRNPH1\",\n      \"pmids\": [\"41867855\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"HNRNPH2 is a nuclear RNA-binding protein that imports into the nucleus via a PY-NLS recognized by Karyopherin-β2/Transportin-1; once nuclear, it binds G-rich sequences and RNA G-quadruplexes in pre-mRNA to regulate alternative splicing of hundreds of targets (including oncogenic splicing switches, myelin protein transcripts, and opioid receptor variants) through cooperative, switch-like mechanisms, and its expression level is itself regulated by alternative splicing feedback involving its paralog HNRNPH1; disease-associated NLS missense mutations disrupt Karyopherin-β2 binding and cause cytoplasmic accumulation with consequent splicing dysregulation and neurodevelopmental disorder, while qRRM mutations impair interaction with the LASR splicing complex.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"HNRNPH2 is a nuclear RNA-binding protein that regulates alternative splicing of pre-mRNA by binding G-rich sequences and RNA G-quadruplexes, governing developmentally and oncogenically important splicing decisions [#0, #2, #11]. It recognizes G-rich enhancer elements—exemplified by the M2 enhancer of PLP/DM20 pre-mRNA in oligodendrocytes—and operates with its paralog hnRNPF to direct splice-site selection [#0]; mechanistically, it unfolds RNA G-quadruplexes to expose clustered G-rich sites, producing indirect cooperativity and switch-like control over hundreds of splicing events [#11]. Through such switches it drives oncogenic splice variants in glioblastoma, promoting the anti-apoptotic MADD isoform and a constitutively active RON kinase variant to support survival and invasion [#1], and it shapes OPRM1 exon 2 inclusion at a G-containing intronic site [#2]. Nuclear import depends on a PY-NLS (residues 204–215, bearing an R-X2-4-P-Y motif and an adjacent DRP epitope) recognized by Karyopherin-β2/Transportin-1 [#7]. De novo missense variants clustering in this NLS reduce Karyopherin-β2 binding and cause cytoplasmic accumulation, defining a neurodevelopmental disorder; knock-in mice recapitulate motor, cognitive, and audiogenic-seizure phenotypes [#3, #6, #7]. HNRNPH2 expression is coupled to its paralog through splicing feedback: it modulates HNRNPH1 pre-mRNA splicing, and antisense-mediated Hnrnph2 knockdown drives compensatory Hnrnph1 upregulation that rescues disease phenotypes in mutant mice [#9]. Additional disease alleles act through distinct routes—the qRRM variant p.Arg114Trp impairs interaction with the LASR splicing complex [#4], and the P213L variant disrupts binding to myelin-related transcripts, impairing oligodendrocyte differentiation and myelination [#10].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Established that hnRNPH2 is a sequence-specific splicing regulator that recognizes G-rich enhancers and selects splice sites, working synergistically with hnRNPF.\",\n      \"evidence\": \"siRNA knockdown, minigene splicing assays, and G-rich mutagenesis in differentiated oligodendrocytes (PLP/DM20)\",\n      \"pmids\": [\"17567613\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define structural basis of G-rich recognition\", \"HNRNPH2-specific versus hnRNPH family contributions not separated\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Connected hnRNPH-controlled splicing switches to cancer cell phenotypes, showing causal roles in survival and invasion via specific oncogenic isoforms.\",\n      \"evidence\": \"siRNA knockdown plus isoform-specific ASO rescue/epistasis in glioblastoma cells with death and invasion readouts\",\n      \"pmids\": [\"21915099\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not distinguish HNRNPH1 from HNRNPH2 contributions\", \"No structural or binding-site map of the regulated exons\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrated direct G-containing sequence binding controls a clinically relevant splice variant and that a single SNP can tune hnRNPH-dependent splicing output.\",\n      \"evidence\": \"EMSA, minigene assays, siRNA/morpholino knockdown, and human postmortem brain analysis at OPRM1 rs9479757\",\n      \"pmids\": [\"25122903\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo physiological consequence of altered hMOR-1 levels not established\", \"Did not resolve paralog-specific binding\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Linked HNRNPH2 NLS variants to a human neurodevelopmental disorder, implicating disrupted nuclear localization.\",\n      \"evidence\": \"Whole-exome sequencing identifying NLS-clustered de novo variants with functional inference\",\n      \"pmids\": [\"27545675\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No direct localization experiment reported in this study\", \"Causality of mislocalization for phenotype not demonstrated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Distinguished two mutational mechanisms—NLS variants impairing shuttling versus a qRRM variant impairing splicing-complex interaction.\",\n      \"evidence\": \"Nucleocytoplasmic shuttling assays, Co-IP for LASR interaction, and RNA-seq of patient fibroblasts\",\n      \"pmids\": [\"34907471\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"LASR interaction shown by Co-IP without structural detail\", \"Causal chain from transcriptome changes to disease unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified Karyopherin-β2 as the import receptor and resolved the PY-NLS structural determinants quantitatively explaining variant mislocalization.\",\n      \"evidence\": \"Structure of Kapβ2•HNRNPH2 complex with site-directed mutagenesis and binding-affinity measurements (preprint)\",\n      \"pmids\": [\"36711837\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Preprint, single lab\", \"Did not test impact on downstream splicing in cells\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showed in vivo that NLS mutations reduce Kapβ2 binding and recapitulate disease phenotypes, and revealed paralog compensation buffering loss of function.\",\n      \"evidence\": \"Two knock-in lines and KO mice, Co-IP for Kapβ2, behavioral/seizure phenotyping, and Hnrnph1 expression analysis\",\n      \"pmids\": [\"37463454\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve toxic gain-of-function versus loss-of-function definitively\", \"Mechanism of failed Hnrnph1 upregulation in knock-ins unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined the splicing-based feedback by which HNRNPH2 controls HNRNPH1 levels and exploited it therapeutically via ASO-driven paralog compensation.\",\n      \"evidence\": \"In vivo ASO knockdown (ICV), RNA-seq/RT-PCR splicing analysis, behavioral rescue, and iPSC-derived neuron validation\",\n      \"pmids\": [\"42018666\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Long-term durability and safety of ASO rescue not established\", \"Full set of co-regulated splicing targets not mapped\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Tied a specific patient mutation to a myelination program, linking impaired target-mRNA binding to oligodendrocyte differentiation defects.\",\n      \"evidence\": \"Hnrnph2P213L knock-in mice, RNA-IP/binding assays, oligodendrocyte differentiation assays, benztropine rescue, and behavioral testing\",\n      \"pmids\": [\"41443536\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab study\", \"Direct target transcripts incompletely catalogued\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Provided a biophysical mechanism—rG4 unfolding generating cooperative multi-site binding—for switch-like control of large splicing programs.\",\n      \"evidence\": \"In vivo/in vitro CLIP-based binding, rG4-unfolding assays, cooperativity modeling, and splicing analysis with patient data (preprint)\",\n      \"pmids\": [\"41867855\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, single lab\", \"Study covers HNRNPH broadly; HNRNPH2-specific cooperativity not isolated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How HNRNPH2's splicing functions, paralog feedback, and post-translational regulation integrate to produce the disorder—and whether the mechanism is gain- or loss-of-function—remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Gain- versus loss-of-function not definitively settled\", \"Cell-type-specific splicing target maps incomplete\", \"Post-translational regulation of HNRNPH2 in humans uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 2, 11]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 1, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [3, 6, 7]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [4, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 1, 11]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [6, 7]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"HNRNPF\", \"TNPO1\", \"HNRNPH1\"],\n    \"other_free_text\": []\n  }\n}\n```","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}