Affinage

FH

Fumarate hydratase, mitochondrial · UniProt P07954

Round 2 corrected
Length
510 aa
Mass
54.6 kDa
Annotated
2026-04-28
130 papers in source corpus 15 papers cited in narrative 15 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FH encodes fumarate hydratase, a mitochondrial TCA cycle enzyme that catalyzes the reversible hydration of fumarate to L-malate and functions as a tumor suppressor whose biallelic inactivation drives oncogenesis through accumulation of the oncometabolite fumarate. Fumarate competitively inhibits α-ketoglutarate-dependent dioxygenases—including histone demethylases (KDMs), TET hydroxylases, and prolyl hydroxylases—causing genome-wide DNA and histone hypermethylation and pseudohypoxic HIF1α stabilization, while also non-enzymatically succinating cysteine residues on ~60 proteins including GAPDH, KEAP1, and ACO2 (PMID:22677546, PMID:25105836). Germline heterozygous FH loss-of-function mutations cause hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome, with tumors showing classical two-hit inactivation and near-complete loss of enzymatic activity (PMID:11865300, PMID:21398687), and also predispose to pheochromocytoma and paraganglioma (PMID:24334767). FH deficiency blocks de novo purine biosynthesis, creating dependence on the purine salvage pathway that represents a therapeutic vulnerability, while co-deletion of the histone chaperone HIRA activates MYC-driven nucleotide metabolism as an additional synthetic vulnerability in FH-null cells (PMID:37255402, PMID:36269833).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2002 High

    Positional cloning established FH as the causative gene for HLRCC syndrome and demonstrated that germline mutations abolish or reduce fumarate hydratase enzymatic activity, identifying the first TCA cycle enzyme to function as a bona fide tumor suppressor.

    Evidence Linkage mapping, mutation identification, and enzymatic activity assays in patient lymphoblastoid cells and tumors across multiple HLRCC families

    PMID:11865300 PMID:12183404

    Open questions at the time
    • Mechanism by which loss of a metabolic enzyme drives tumorigenesis was unknown
    • Whether FH loss contributes to sporadic (non-syndromic) tumors was unclear
    • No animal model existed to test consequences of FH loss in vivo
  2. 2004 Medium

    The discovery of biallelic somatic FH inactivation in sporadic uterine leiomyomas confirmed FH as a driver of non-hereditary tumors and showed that FH-deficient leiomyomas represent a distinct molecular subtype from MED12-mutant tumors.

    Evidence LOH analysis and Sanger sequencing of FH in sporadic leiomyomas; later confirmed by mutual exclusivity with MED12 and HMGA2 alterations across large tumor series

    PMID:14695314 PMID:27187686 PMID:28592321

    Open questions at the time
    • Whether FH-deficient leiomyomas can progress to leiomyosarcoma remained uncertain
    • Tissue-specific mechanisms favoring smooth muscle tumorigenesis were not defined
  3. 2007 Medium

    Demonstration of HIF1α stabilization in FH-deficient tumors provided the first evidence that fumarate accumulation inhibits prolyl hydroxylases to create pseudohypoxia, linking metabolite accumulation to an oncogenic signaling phenotype.

    Evidence HIF1α immunohistochemistry in HLRCC tumor series with microsatellite instability analysis

    PMID:17520677

    Open questions at the time
    • Whether HIF1α stabilization was the primary oncogenic driver or one of several parallel mechanisms was unclear
    • Direct measurement of PHD inhibition by fumarate in these tumors was lacking
  4. 2011 Medium

    Systematic functional characterization of 21 novel FH mutations confirmed that reduced enzymatic activity is the universal pathogenic mechanism across all mutation types, establishing a functional assay framework for variant classification.

    Evidence Sanger sequencing and direct FH enzymatic activity assay across 56 HLRCC families

    PMID:21398687

    Open questions at the time
    • Many variants of uncertain significance remained uncharacterized
    • Quantitative relationship between residual FH activity and tumor risk was not established
  5. 2012 High

    The mechanistic basis of fumarate-driven oncogenesis was broadened beyond pseudohypoxia by demonstrating that fumarate competitively inhibits the entire family of α-KG-dependent dioxygenases, including histone demethylases and TET enzymes, causing genome-wide epigenetic reprogramming.

    Evidence In vitro enzymatic inhibition assays, siRNA knockdown of FH with metabolite quantification, ectopic expression of tumor-derived FH mutants with histone methylation and 5-hmC readouts

    PMID:22677546

    Open questions at the time
    • Which specific epigenetic changes are causally required for transformation versus bystanders was not resolved
    • Whether epigenetic changes are reversible upon FH reconstitution was not tested
  6. 2013 High

    FH was established as a pheochromocytoma/paraganglioma susceptibility gene with the same fumarate-driven epigenetic and succination signatures as seen in SDH-mutant tumors, expanding the clinical spectrum of FH deficiency beyond HLRCC.

    Evidence Germline sequencing, MLPA, immunohistochemistry for 5-hmC and 2SC in FH-mutant PCC/PGL cohort

    PMID:24334767

    Open questions at the time
    • Why FH mutations only rarely cause PCC/PGL compared to SDH mutations was unexplained
    • Genotype-phenotype correlations distinguishing HLRCC-only from HLRCC+PCC/PGL families were not established
  7. 2014 Medium

    Proteomic profiling revealed that fumarate-mediated protein succination is widespread (~60 targets), irreversibly modifying functionally critical cysteines on GAPDH, KEAP1, and ACO2, establishing protein succination as a major effector mechanism of FH-deficient oncogenesis alongside epigenetic reprogramming.

    Evidence Mass spectrometry-based succination screen on FH-mutant tumor tissue and HLRCC cell lines

    PMID:25105836

    Open questions at the time
    • The individual contributions of specific succination events to tumorigenesis were not dissected
    • Whether succination targets differ across tissue types was not tested
  8. 2016 Medium

    An FH-knockout rat model demonstrated that complete FH loss is embryonically lethal while heterozygous loss causes renal dysplasia and hematopoietic defects, providing the first in vivo genetic evidence that partial FH deficiency has cell-autonomous pathological consequences in kidney epithelium.

    Evidence TALEN-mediated FH knockout in rats with histopathology, IHC, and hematologic/biochemical analysis

    PMID:27556703

    Open questions at the time
    • The rat model did not recapitulate frank tumor formation characteristic of HLRCC
    • Whether the renal dysplastic foci progress to carcinoma with aging was not determined
  9. 2022 High

    A genome-wide CRISPR screen identified HIRA loss as a synthetic vulnerability partner in FH-deficient cells, operating through MYC activation and enhanced nucleotide metabolism independent of HIRA's histone chaperone function, revealing a non-canonical cooperation between chromatin regulation and metabolic rewiring.

    Evidence CRISPR-Cas9 screen in Fh1-null mouse cells; in vitro/in vivo validation; transcriptomic and nucleotide metabolism assays

    PMID:36269833

    Open questions at the time
    • Whether HIRA loss occurs spontaneously in human HLRCC tumors was not established
    • The mechanism linking HIRA loss to MYC activation was not fully defined
    • Therapeutic targeting of this synthetic interaction was not demonstrated
  10. 2023 High

    Fumarate accumulation was shown to block de novo purine biosynthesis by inhibiting adenylosuccinate lyase, creating a targetable dependence on the purine salvage pathway that was exploited therapeutically with 6-mercaptopurine in vivo; in parallel, systematic enzymatic characterization of 74 FH variants of uncertain significance classified over half as pathogenic.

    Evidence Isotope tracing of purine metabolism, enzymatic characterization of 74 FH variants, genetic and pharmacologic purine salvage inhibition in HLRCC xenografts

    PMID:37255402

    Open questions at the time
    • Clinical efficacy of purine salvage inhibition in HLRCC patients has not been tested
    • Whether purine synthesis blockade cooperates with epigenetic or succination mechanisms in driving tumor phenotypes is unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • The tissue-specific determinants of aggressive FH-deficient tumorigenesis (e.g., why HLRCC renal tumors are particularly lethal) and the relative causal contributions of epigenetic reprogramming, protein succination, and metabolic rewiring to tumor initiation versus progression remain unresolved.
  • No genetically faithful HLRCC mouse model recapitulates full-spectrum renal cell carcinoma
  • Causal hierarchy among pseudohypoxia, epigenetic changes, succination, and purine metabolism disruption is not established
  • Tissue-specific cofactors that determine tumor spectrum in FH mutation carriers are unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016829 lyase activity 4
Localization
GO:0005739 mitochondrion 2
Pathway
R-HSA-1430728 Metabolism 3 R-HSA-1643685 Disease 3 R-HSA-4839726 Chromatin organization 2
Partners
ACO2GAPDHHIF1AHIRAKEAP1

Evidence

Reading pass · 15 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 Germline mutations in the FH gene (encoding fumarate hydratase, a TCA cycle enzyme) cause dominantly inherited uterine fibroids, cutaneous leiomyomata, and papillary renal cell cancer (HLRCC syndrome). Leiomyomatosis-associated mutations predict absent/truncated protein or substitutions of conserved amino acids; fumarate hydratase enzymatic activity is reduced in lymphoblastoid cells from affected individuals and is very low or absent in tumors, establishing FH as a tumor suppressor. Positional cloning, germline mutation identification, enzymatic activity assay in lymphoblastoid cells and tumor tissue Nature genetics High 11865300
2002 Biallelic inactivation of FH (fumarate hydratase) is rare in sporadic counterparts of HLRCC-associated tumor types; one uterine leiomyosarcoma, one cutaneous leiomyoma, and one soft tissue sarcoma showed biallelic FH inactivation, with the sarcoma representing purely somatic inactivation, confirming FH as a classical two-hit tumor suppressor. Mutation screening, loss of heterozygosity analysis across multiple tumor types Cancer research Medium 12183404
2004 Somatic FH mutations (a splice site change causing exon 4 deletion and a missense mutation Ala196Thr) occur in nonsyndromic uterine leiomyomas showing LOH at 1q43, confirming FH as a bona fide target of 1q43 deletions and demonstrating that biallelic somatic FH inactivation drives non-hereditary leiomyoma formation. LOH analysis, Sanger sequencing of FH in 299 malignant tumors and 153 leiomyomas The American journal of pathology Medium 14695314
2007 FH-deficient (HLRCC) tumors show moderately or highly stabilized HIF1α in 67% of cases, consistent with fumarate accumulation inhibiting prolyl hydroxylases (PHDs) and causing pseudohypoxia; however, HIF1α stabilization in these tumors does not cause microsatellite instability or loss of MSH2, dissociating HIF1α stabilization from mismatch repair deficiency in this context. Immunohistochemistry for HIF1α and MSH2 in HLRCC tumor series; microsatellite instability analysis International journal of cancer Medium 17520677
2012 Fumarate (accumulated due to FH loss) and succinate are competitive inhibitors of multiple α-ketoglutarate (α-KG)-dependent dioxygenases, including histone demethylases (KDMs), TET family 5mC hydroxylases, and prolyl hydroxylases. Knockdown of FH elevates intracellular fumarate which broadly inhibits α-KG-dependent dioxygenase activity; ectopic expression of tumor-derived FH mutants inhibits histone demethylation and 5mC hydroxylation, leading to genome-wide hypermethylation. In vitro enzymatic inhibition assays, siRNA knockdown of FH with metabolite measurement, ectopic expression of FH mutants, histone methylation and 5-hmC assays Genes & development High 22677546
2013 Germline FH mutations predispose to malignant pheochromocytoma and paraganglioma. FH-deficient PCC/PGLs show somatic second-hit inactivation, loss of fumarate hydratase enzymatic activity, low 5-hydroxymethylcytosine (5-hmC) levels (consistent with TET inhibition by fumarate), and positive 2SC (S-(2-succino)cysteine) immunostaining indicative of protein succination, demonstrating the same epigenetic deregulation pattern as SDHB-mutated tumors. Germline sequencing, MLPA for large deletions, immunohistochemistry for 5-hmC and 2SC, enzymatic activity confirmed by second-hit somatic analysis Human molecular genetics High 24334767
2014 Proteomic screening of FH-mutant tumors and HLRCC-derived cell lines identified 60 proteins with succinated cysteine residues (S-(2-succino)cysteine, 2SC), a non-enzymatic irreversible modification of cysteine by fumarate. Key succinated targets include GAPDH, KEAP1, and mitochondrial aconitase (ACO2) at functionally significant cysteines; bioinformatic analysis shows most succinated targets are involved in redox signaling, demonstrating that fumarate acts as an oncometabolite through widespread protein succination. Mass spectrometry-based proteomic succination screen on FH-mutant tumor tissue and HLRCC cell lines Metabolites Medium 25105836
2016 Homozygous FH knockout in rats is embryonically lethal; heterozygous FH+/- rats display hematopoietic and kidney dysfunction, and small foci of anaplastic tubular epithelial cells in the kidney that are positive for Ki67, p53, and Sox9, demonstrating that partial FH loss causes renal dysplasia and functional organ defects in vivo. TALEN-mediated FH gene knockout rat model; histopathology, immunohistochemistry (Ki67, p53, Sox9), hematology and biochemical analyses Oncotarget Medium 27556703
2016 Somatic MED12 mutations and biallelic FH inactivation are mutually exclusive in both HLRCC-associated and sporadic uterine leiomyomas, and FH-deficient tumors cluster separately from MED12-mutant tumors by global gene expression profiling, indicating they represent distinct molecular subtypes driven by different oncogenic pathways. MED12 mutation screening, 2SC immunohistochemistry for FH deficiency, Affymetrix gene expression arrays British journal of cancer Medium 27187686
2017 MED12, HMGA2, and FH alterations are mutually exclusive driver alterations in uterine smooth muscle tumors. FH-deficient tumors are the predominant driver in leiomyomas with bizarre nuclei, while MED12 mutations predominate in conventional and mitotically active leiomyomas; presence of these leiomyoma driver alterations in ~one-third of leiomyosarcomas suggests potential progression from precursor lesions. FH immunohistochemistry (2SC), MED12 mutation screening, HMGA2 expression analysis across 210 uterine smooth muscle tumors Molecular cancer Medium 28592321
2021 FH encodes a mitochondrial enzyme catalyzing the reversible hydration of fumarate to L-malate in the TCA cycle. FH deficiency drives oncogenesis through multiple mechanisms: promotion of aerobic glycolysis (Warburg effect), induction of pseudohypoxia (via PHD inhibition and HIF stabilization), post-translational protein succination, and impairment of DNA damage repair by homologous recombination. Review synthesizing mechanistic experimental data from multiple prior studies Journal of clinical pathology Medium 34353877
2022 HIRA loss enhances proliferation and invasion of Fh1-deficient cells in vitro and in vivo. Mechanistically, Hira loss activates MYC and its target genes, specifically increasing nucleotide metabolism in Fh1-deficient cells independent of HIRA's histone chaperone activity, identifying a synthetic vulnerabilty in FH-deficient cells. Genome-wide CRISPR-Cas9 screen in Fh1-deficient mouse cells; in vitro proliferation/invasion assays; in vivo tumor models; transcriptomic analysis of MYC targets; nucleotide metabolism assays Science advances High 36269833
2023 Fumarate accumulation due to FH loss blocks de novo purine biosynthesis, rendering FH-deficient cells dependent on the purine salvage pathway for proliferation. Genetic or pharmacologic inhibition of purine salvage (including 6-mercaptopurine) reduced HLRCC tumor growth in vivo. Functional characterization of 74 FH variants of uncertain significance showed that over half are enzymatically inactive. Catalytic efficiency measurement of 74 FH variants; isotope tracing of purine biosynthesis; genetic knockdown and pharmacologic inhibition of purine salvage in HLRCC cell lines; in vivo xenograft models Cancer discovery High 37255402
2023 FH loss, via fumarate accumulation, activates multiple oncogenic cascades contributing to tumorigenesis including pseudohypoxia, epigenetic reprogramming through α-KG-dependent dioxygenase inhibition, protein succination, and metabolic rewiring; the tissue-specific aggressive behavior of HLRCC cancers remains under investigation. Review integrating mechanistic experimental findings from the field British journal of cancer Medium 37689804
2011 Novel FH mutations across 56 HLRCC families and isolated papillary RCC patients demonstrated that all 21 novel mutations are deleterious by significant reduction of FH enzymatic activity; reduced FH activity was the functional correlate for pathogenicity of missense, frameshift, nonsense, splice site, and deletion variants. Sanger sequencing, functional FH enzymatic activity assay in patient-derived samples Journal of medical genetics Medium 21398687

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 Complement factor H polymorphism in age-related macular degeneration. Science (New York, N.Y.) 3310 15761122
2005 Complement factor H polymorphism and age-related macular degeneration. Science (New York, N.Y.) 1965 15761121
2005 Complement factor H variant increases the risk of age-related macular degeneration. Science (New York, N.Y.) 1959 15761120
2005 A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration. Proceedings of the National Academy of Sciences of the United States of America 1646 15870199
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2002 Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. Nature genetics 1204 11865300
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2012 Inhibition of α-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors. Genes & development 920 22677546
2010 Relative role of genetic complement abnormalities in sporadic and familial aHUS and their impact on clinical phenotype. Clinical journal of the American Society of Nephrology : CJASN 773 20595690
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2013 Seven new loci associated with age-related macular degeneration. Nature genetics 649 23455636
2005 Hypothetical LOC387715 is a second major susceptibility gene for age-related macular degeneration, contributing independently of complement factor H to disease risk. Human molecular genetics 640 16174643
2006 Genetics of HUS: the impact of MCP, CFH, and IF mutations on clinical presentation, response to treatment, and outcome. Blood 555 16621965
2011 Genome-wide association study identifies susceptibility loci for IgA nephropathy. Nature genetics 522 21399633
2013 Immunology of age-related macular degeneration. Nature reviews. Immunology 514 23702979
1994 Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides. Gene 492 8125298
2006 Common variation in three genes, including a noncoding variant in CFH, strongly influences risk of age-related macular degeneration. Nature genetics 489 16936732
2004 The human complement factor H: functional roles, genetic variations and disease associations. Molecular immunology 447 15163532
2011 Complement factor H binds malondialdehyde epitopes and protects from oxidative stress. Nature 445 21979047
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2010 Genetic variants near TIMP3 and high-density lipoprotein-associated loci influence susceptibility to age-related macular degeneration. Proceedings of the National Academy of Sciences of the United States of America 433 20385819
1998 Genetic studies into inherited and sporadic hemolytic uremic syndrome. Kidney international 390 9551389
2010 Genome-wide association study of advanced age-related macular degeneration identifies a role of the hepatic lipase gene (LIPC). Proceedings of the National Academy of Sciences of the United States of America 376 20385826
2005 Human plasma N-glycoproteome analysis by immunoaffinity subtraction, hydrazide chemistry, and mass spectrometry. Journal of proteome research 350 16335952
2007 Variation in complement factor 3 is associated with risk of age-related macular degeneration. Nature genetics 344 17767156
2006 The meningococcal vaccine candidate GNA1870 binds the complement regulatory protein factor H and enhances serum resistance. Journal of immunology (Baltimore, Md. : 1950) 330 16785547
2010 Complement control protein factor H: the good, the bad, and the inadequate. Molecular immunology 319 20580090
2013 Germline mutations in FH confer predisposition to malignant pheochromocytomas and paragangliomas. Human molecular genetics 315 24334767
2008 Systemic complement activation in age-related macular degeneration. PloS one 310 18596911
1988 The complete amino acid sequence of human complement factor H. The Biochemical journal 309 2963625
2015 LEF-1 and TCF-1 orchestrate T(FH) differentiation by regulating differentiation circuits upstream of the transcriptional repressor Bcl6. Nature immunology 286 26214741
2015 The transcription factor TCF-1 initiates the differentiation of T(FH) cells during acute viral infection. Nature immunology 198 26214740
2018 Circulating TFH cells, serological memory, and tissue compartmentalization shape human influenza-specific B cell immunity. Science translational medicine 191 29444980
2021 Bcl6-Mediated Transcriptional Regulation of Follicular Helper T cells (TFH). Trends in immunology 146 33663954
2013 MicroRNAs of the miR-17∼92 family are critical regulators of T(FH) differentiation. Nature immunology 144 23812097
2004 Biallelic inactivation of fumarate hydratase (FH) occurs in nonsyndromic uterine leiomyomas but is rare in other tumors. The American journal of pathology 135 14695314
2008 The FH mutation database: an online database of fumarate hydratase mutations involved in the MCUL (HLRCC) tumor syndrome and congenital fumarase deficiency. BMC medical genetics 126 18366737
2002 Few FH mutations in sporadic counterparts of tumor types observed in hereditary leiomyomatosis and renal cell cancer families. Cancer research 125 12183404
2018 Recognition of microbial viability via TLR8 drives TFH cell differentiation and vaccine responses. Nature immunology 121 29556002
2017 Tfr cells lack IL-2Rα but express decoy IL-1R2 and IL-1Ra and suppress the IL-1-dependent activation of Tfh cells. Science immunology 120 28887367
2017 PTEN, DICER1, FH, and Their Associated Tumor Susceptibility Syndromes: Clinical Features, Genetics, and Surveillance Recommendations in Childhood. Clinical cancer research : an official journal of the American Association for Cancer Research 119 28620008
2010 Follicular lymphoma cell niche: identification of a preeminent IL-4-dependent T(FH)-B cell axis. Leukemia 117 20944673
2021 Metabolic control of TFH cells and humoral immunity by phosphatidylethanolamine. Nature 111 34234346
1998 cyk-1: a C. elegans FH gene required for a late step in embryonic cytokinesis. Journal of cell science 110 9645949
2011 Novel FH mutations in families with hereditary leiomyomatosis and renal cell cancer (HLRCC) and patients with isolated type 2 papillary renal cell carcinoma. Journal of medical genetics 106 21398687
2019 Inhibition of IL-2 responsiveness by IL-6 is required for the generation of GC-TFH cells. Science immunology 103 31519812
2015 Clinical experience of scoring criteria for Familial Hypercholesterolaemia (FH) genetic testing in Wales. Atherosclerosis 102 25797312
2021 Dynamic regulation of TFH selection during the germinal centre reaction. Nature 88 33536617
2022 Targeting TFH cells in human diseases and vaccination: rationale and practice. Nature immunology 83 35817844
2023 Fumarate hydratase (FH) and cancer: a paradigm of oncometabolism. British journal of cancer 82 37689804
2019 Excessive CD11c+Tbet+ B cells promote aberrant TFH differentiation and affinity-based germinal center selection in lupus. Proceedings of the National Academy of Sciences of the United States of America 82 31451659
2017 Half a Century Tales of Familial Hypercholesterolemia (FH) in Japan. Journal of atherosclerosis and thrombosis 80 28179607
2003 Electronegative LDL of FH subjects: chemical characterization and induction of chemokine release from human endothelial cells. Atherosclerosis 80 12535738
2017 Characterization of MED12, HMGA2, and FH alterations reveals molecular variability in uterine smooth muscle tumors. Molecular cancer 76 28592321
2005 Autosomal recessive hypercholesterolemia (ARH) and homozygous familial hypercholesterolemia (FH): a phenotypic comparison. Atherosclerosis 76 16343504
2020 Immunophenotyping in pemphigus reveals a TH17/TFH17 cell-dominated immune response promoting desmoglein1/3-specific autoantibody production. The Journal of allergy and clinical immunology 74 33221382
2017 Increased cathepsin S in Prdm1-/- dendritic cells alters the TFH cell repertoire and contributes to lupus. Nature immunology 72 28692065
2016 The Montreal-FH-SCORE: A new score to predict cardiovascular events in familial hypercholesterolemia. Journal of clinical lipidology 71 28391914
2016 Human regulatory B cells control the TFH cell response. The Journal of allergy and clinical immunology 69 27865860
1988 Characterization of six partial deletions in the low-density-lipoprotein (LDL) receptor gene causing familial hypercholesterolemia (FH). American journal of human genetics 68 2837085
2020 Dual function of Langerhans cells in skin TSLP-promoted TFH differentiation in mouse atopic dermatitis. The Journal of allergy and clinical immunology 66 33068561
2018 Ezh2 programs TFH differentiation by integrating phosphorylation-dependent activation of Bcl6 and polycomb-dependent repression of p19Arf. Nature communications 61 30575739
2017 Critical Role for Skin-Derived Migratory DCs and Langerhans Cells in TFH and GC Responses after Intradermal Immunization. The Journal of investigative dermatology 60 28457909
2004 Molecular genetic analysis of FIH-1, FH, and SDHB candidate tumour suppressor genes in renal cell carcinoma. Journal of clinical pathology 57 15220362
2021 Dysregulation of TFH-B-TRM lymphocyte cooperation is associated with unfavorable anti-PD-1 responses in EGFR-mutant lung cancer. Nature communications 54 34663810
2014 Human factor H (FH) impairs protective meningococcal anti-FHbp antibody responses and the antibodies enhance FH binding. mBio 53 25161192
2020 Ethanol consumption inhibits TFH cell responses and the development of autoimmune arthritis. Nature communications 52 32332730
2014 The Succinated Proteome of FH-Mutant Tumours. Metabolites 52 25105836
2019 TFH cells in bystander and cognate interactions with B cells. Immunological reviews 49 30874359
2000 Complement factor H: sequence analysis of 221 kb of human genomic DNA containing the entire fH, fHR-1 and fHR-3 genes. Molecular immunology 49 10781834
1998 Concentrations of the atherogenic Lp(a) are elevated in FH. European journal of human genetics : EJHG 49 9781014
2018 Fumarate hydratase (FH) deficiency in uterine leiomyomas: recognition by histological features versus blind immunoscreening. Virchows Archiv : an international journal of pathology 48 29332133
2022 Genomic Profiling and Response to Immune Checkpoint Inhibition plus Tyrosine Kinase Inhibition in FH-Deficient Renal Cell Carcinoma. European urology 46 35715365
2020 The emerging role of T follicular helper (TFH) cells in aging: Influence on the immune frailty. Ageing research reviews 41 32344191
2019 Rare Functional Variants in Complement Genes and Anti-FH Autoantibodies-Associated aHUS. Frontiers in immunology 41 31118930
2016 MED12 mutations and FH inactivation are mutually exclusive in uterine leiomyomas. British journal of cancer 40 27187686
1988 New variant of low density lipoprotein receptor gene. FH-Tonami. Arteriosclerosis (Dallas, Tex.) 40 2831865
2017 The utility of SDHB and FH immunohistochemistry in patients evaluated for hereditary paraganglioma-pheochromocytoma syndromes. Human pathology 39 29079178
2023 MAIT cells activate dendritic cells to promote TFH cell differentiation and induce humoral immunity. Cell reports 38 36989114
2015 In vitro assay to sensitively measure T(FR) suppressive capacity and T(FH) stimulation of B cell responses. Methods in molecular biology (Clifton, N.J.) 37 25836309
2023 FH Variant Pathogenicity Promotes Purine Salvage Pathway Dependence in Kidney Cancer. Cancer discovery 36 37255402
2021 The metabolic hormone leptin promotes the function of TFH cells and supports vaccine responses. Nature communications 36 34031386
2019 HnRNP F/H associate with hTERC and telomerase holoenzyme to modulate telomerase function and promote cell proliferation. Cell death and differentiation 34 31863069
2021 Tox2 is required for the maintenance of GC TFH cells and the generation of memory TFH cells. Science advances 33 34623911
2018 Complement Inhibitor CRIg/FH Ameliorates Renal Ischemia Reperfusion Injury via Activation of PI3K/AKT Signaling. Journal of immunology (Baltimore, Md. : 1950) 33 30429287
2019 Current Status of Familial Hypercholesterolemia in China: A Need for Patient FH Registry Systems. Frontiers in physiology 32 30949068
2019 Fumarate hydratase FH c.1431_1433dupAAA (p.Lys477dup) variant is not associated with cancer including renal cell carcinoma. Human mutation 32 31444830
2017 Delivery of CR2-fH Using AAV Vector Therapy as Treatment Strategy in the Mouse Model of Choroidal Neovascularization. Molecular therapy. Methods & clinical development 32 29234687
2021 TFH cells depend on Tcf1-intrinsic HDAC activity to suppress CTLA4 and guard B-cell help function. Proceedings of the National Academy of Sciences of the United States of America 31 33372138
2020 Human pregnancy levels of estrogen and progesterone contribute to humoral immunity by activating TFH /B cell axis. European journal of immunology 31 33012073
2022 CXCL13 expressed on inflamed cerebral blood vessels recruit IL-21 producing TFH cells to damage neurons following stroke. Journal of neuroinflammation 29 35624463
2024 Stem-like progenitor and terminally differentiated TFH-like CD4+ T cell exhaustion in the tumor microenvironment. Cell reports 28 38363680
2017 Immunohistochemical Characterization of Fumarate Hydratase (FH) and Succinate Dehydrogenase (SDH) in Cutaneous Leiomyomas for Detection of Familial Cancer Syndromes. The American journal of surgical pathology 28 28288038
2015 Binding of Complement Factor H (FH) Decreases Protective Anti-FH Binding Protein Antibody Responses of Infant Rhesus Macaques Immunized With a Meningococcal Serogroup B Vaccine. The Journal of infectious diseases 28 25676468
2021 Gene of the month: FH. Journal of clinical pathology 26 34353877
2024 TGF-β specifies TFH versus TH17 cell fates in murine CD4+ T cells through c-Maf. Science immunology 25 38427718
2022 Comparison of 2SC, AKR1B10, and FH Antibodies as Potential Biomarkers for FH-deficient Uterine Leiomyomas. The American journal of surgical pathology 23 34678832
2021 Follicular Helper T (TFH) Cell Targeting by TLR8 Signaling For Improving HBsAg-Specific B Cell Response In Chronic Hepatitis B Patients. Frontiers in immunology 22 34512670
2013 [Diagnostic and treatment of familial hypercholesterolemia (FH) in adult: guidelines from the New French Society of Atherosclerosis (NSFA)]. Presse medicale (Paris, France : 1983) 22 23578468
2007 Increased HIF1 alpha in SDH and FH deficient tumors does not cause microsatellite instability. International journal of cancer 22 17520677
2023 Aiolos represses CD4+ T cell cytotoxic programming via reciprocal regulation of TFH transcription factors and IL-2 sensitivity. Nature communications 21 36964178
2022 Genomic and Metabolic Hallmarks of SDH- and FH-deficient Renal Cell Carcinomas. European urology focus 21 35288096
2017 The Genetic Spectrum of Familial Hypercholesterolemia (FH) in the Iranian Population. Scientific reports 21 29213121
1992 A large deletion in the LDL receptor gene--the cause of familial hypercholesterolemia in three Italian families: a study that dates back to the 17th century (FH-Pavia). American journal of human genetics 21 1609792
2019 Circulating PCSK9 and cardiovascular events in FH patients with standard lipid-lowering therapy. Journal of translational medicine 20 31711505
2019 The new complement inhibitor CRIg/FH ameliorates lupus nephritis in lupus-prone MRL/lpr mice. BMC nephrology 20 31752725
2017 The Spectrum of Familial Hypercholesterolemia (FH) in Saudi Arabia: Prime Time for Patient FH Registry. The open cardiovascular medicine journal 19 28868092
2023 The transcription factor Mef2d regulates B:T synapse-dependent GC-TFH differentiation and IL-21-mediated humoral immunity. Science immunology 18 36961907
2022 Strong influenza-induced TFH generation requires CD4 effectors to recognize antigen locally and receive signals from continuing infection. Proceedings of the National Academy of Sciences of the United States of America 18 35177472
2023 Prevalence of FH-Causing Variants and Impact on LDL-C Concentration in European, South Asian, and African Ancestry Groups of the UK Biobank-Brief Report. Arteriosclerosis, thrombosis, and vascular biology 17 37409534
2018 Comparative analysis of AKT and the related biomarkers in uterine leiomyomas with MED12, HMGA2, and FH mutations. Genes, chromosomes & cancer 17 29790226
2012 Maternal familial hypercholesterolaemia (FH) confers altered haemostatic profile in offspring with and without FH. Thrombosis research 16 23199546
2006 Modulation of high alcohol drinking in the inbred Fawn-Hooded (FH/Wjd) rat strain: implications for treatment. Addiction biology 16 16961764
2005 Altered composition of HDL3 in FH subjects causing a HDL subfraction with less atheroprotective function. Clinica chimica acta; international journal of clinical chemistry 16 15936009
2023 SARS-CoV-2 spike-specific TFH cells exhibit unique responses in infected and vaccinated individuals. Signal transduction and targeted therapy 15 37802996
2022 Kidney tumors associated with germline mutations of FH and SDHB show a CpG island methylator phenotype (CIMP). PloS one 15 36455002
2017 The Drosophila hnRNP F/H Homolog Glorund Uses Two Distinct RNA-Binding Modes to Diversify Target Recognition. Cell reports 15 28380354
2019 TH1-Polarized TFH Cells Delay Naturally-Acquired Immunity to Malaria. Frontiers in immunology 14 31156642
2017 Analysis of LDLR variants from homozygous FH patients carrying multiple mutations in the LDLR gene. Atherosclerosis 14 28645073
2022 Clonal evolution and TCR specificity of the human TFH cell response to Plasmodium falciparum CSP. Science immunology 13 35687696
2022 Exploring the mechanism of berberine-mediated Tfh cell immunosuppression. Phytomedicine : international journal of phytotherapy and phytopharmacology 13 35901597
2021 Zn2+-dependent enhancement of Atrazine biodegradation by Klebsiella variicola FH-1. Journal of hazardous materials 13 33858092
2012 The impact of severe LDL receptor mutations on SREBP-pathway regulation in homozygous familial hypercholesterolemia (FH). Gene 13 22425645
2022 HIRA loss transforms FH-deficient cells. Science advances 12 36269833
2025 Mitochondrial DNA oxidation propagates autoimmunity by enabling plasmacytoid dendritic cells to induce TFH differentiation. Nature immunology 11 40528028
2020 Prevalence Of familial hypercholeSTerolaemia (FH) in Italian Patients with coronary artERy disease: The POSTER study. Atherosclerosis 11 32823190
2016 Generation of TALEN-mediated FH knockout rat model. Oncotarget 11 27556703