Affinage

OTC

Ornithine transcarbamylase, mitochondrial · UniProt P00480

Length
354 aa
Mass
39.9 kDa
Annotated
2026-06-10
100 papers in source corpus 26 papers cited in narrative 26 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

OTC encodes the mitochondrial enzyme ornithine transcarbamylase, which catalyzes the condensation of carbamoyl phosphate with ornithine to form citrulline and functions as a rate-controlling step of hepatic ureagenesis, ammonia detoxification, and downstream arginine/nitric oxide synthesis (PMID:18697914, PMID:37146589). Enzymatic competence depends on intact active-site and core-domain residues: structure-guided and deep-mutational-scanning analyses show that core/active-site substitutions cause complete loss of activity and neonatal-onset disease, whereas surface mutations confer partial activity and late onset, and a large-scale functional screen across 1,570 missense substitutions resolved benign from pathogenic alleles and defined a 13-residue 'SMG loop' required for activity (PMID:17334707, PMID:37146589). Some pathogenic alleles (e.g. P225L) retain normal kinetics and stability but yield undetectable protein, indicating loss through degradation of the mutant precursor during mitochondrial import rather than catalytic failure (PMID:9427144, PMID:10448647). Liver-specific OTC expression is set by promoter–enhancer cooperation through a conserved HNF4α binding site, and regulatory variants that disrupt this interaction (c.-366A>G, c.-106C>A) reduce transcription and can cause hyperammonemia under metabolic stress (PMID:20127982, PMID:35605046). Functional ureagenic capacity in heterozygous females is governed by X-inactivation mosaicism: the proportion of OTC-expressing hepatocytes correlates directly with liver activity, and a cellular threshold of roughly 20–30% OTC-positive hepatocytes is required for metabolic stability, establishing that the distribution of activity across cells—not merely total activity—determines ammonia detoxification (PMID:2049185, PMID:29623395, PMID:24108150). Beyond the liver, OTC-derived citrulline supports de novo arginine synthesis and basal nitric oxide production, including in a subset of nNOS-positive nitrergic neurons (PMID:18697914, PMID:28868581).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 1991 Medium

    Established that the OTC gene product is enzymatically functional in vivo and that intestinal OTC, not only hepatic OTC, contributes to nitrogen metabolism, addressing whether the cloned gene encodes the active urea-cycle enzyme.

    Evidence Transgenic rescue of OTC-deficient spf-ash mice with liver/intestinal-promoter rat OTC cDNA; enzyme activity and urinary orotic acid

    PMID:2001730 PMID:7827141

    Open questions at the time
    • Relative tissue contributions defined in mouse, not directly quantified in human
    • Mechanism of intestinal OTC handling of nitrogen flux not detailed
  2. 1991 Medium

    Showed that residual OTC activity in carrier livers tracks the fraction of OTC-expressing hepatocytes set by X-inactivation, and that gene activation requires trans-acting hepatocyte-specific factors rather than demethylation alone.

    Evidence Anti-OTC immunofluorescence with enzymatic correlation in heterozygous spf-ash mice; cell-fusion complementation of silent hepatoma OTC

    PMID:1860901 PMID:2049185

    Open questions at the time
    • Identity of the hepatocyte-specific trans-acting factors not resolved here
    • Quantitative cellular threshold not yet defined
  3. 1993 Low

    Began mapping genotype to phenotype by linking active-site/core-domain mutations to neonatal-onset complete deficiency and surface mutations to late-onset partial deficiency.

    Evidence PCR-SSCP and sequencing across patients; genotype-phenotype correlation

    PMID:8365726

    Open questions at the time
    • Pathogenicity inferred from correlation without in vitro enzyme reconstitution
    • Mechanism of partial vs complete loss not biochemically distinguished
  4. 1997 Medium

    Distinguished catalytic defects from protein-stability/import defects, showing some mutants (P225L) are kinetically normal but undetectable, implicating precursor degradation during mitochondrial import.

    Evidence Liver OTC antigen quantification, kinetic (Km, pH) and thermal stability analysis of mutant enzyme; COS1 expression of L148F

    PMID:9056557 PMID:9427144

    Open questions at the time
    • Direct demonstration of precursor degradation pathway not provided
    • Import machinery components not identified
  5. 1999 Medium

    Identified species-specific differences in mitochondrial import of OTC precursor and showed that restoring OTC activity corrects secondary mitochondrial protein abnormalities.

    Evidence EM immunolocalization, subcellular fractionation, and activity assay after adenoviral OTC delivery in spf-ash mice

    PMID:10448647

    Open questions at the time
    • Molecular basis of the human precursor translocation block unresolved
    • Implications for human gene therapy not directly tested
  6. 2006 Medium

    Demonstrated that substrate availability and amino-acid balance, not just enzyme level, are rate-limiting for ureagenesis in the partially deficient state.

    Evidence Stable isotope tracer urea kinetics in spf-ash mice with ornithine and balanced amino acid supplementation

    PMID:16549467 PMID:16772445

    Open questions at the time
    • Findings in mouse partial-deficiency model; human dietary thresholds not defined
    • Mechanism of substrate channeling not addressed
  7. 2008 High

    Established OTC's role beyond ureagenesis, showing it supports de novo arginine synthesis and basal nitric oxide production via the citrulline-arginine pathway.

    Evidence Multiple stable isotope tracers measured by LC-MS for in vivo NO and arginine flux in spf-ash mice, with LPS challenge

    PMID:18697914

    Open questions at the time
    • Tissue-specific contributions to systemic NO not dissected
    • Relevance to human nitrergic signaling inferred separately
  8. 2010 Medium

    Defined OTC transcriptional control as requiring promoter-enhancer cooperation, with a regulatory variant disrupting that interaction.

    Evidence Dual-luciferase reporter assays and transcription start site mapping for the c.-366A>G variant

    PMID:20127982

    Open questions at the time
    • Enhancer-binding factors not yet identified at this stage
    • In vivo expression effect not measured
  9. 2009 Medium

    Identified hepatocyte proliferation as a specific barrier to durable OTC gene therapy, since dividing neonatal hepatocytes dilute episomal vector.

    Evidence AAV2/8 murine OTC delivery to adult vs neonatal spf-ash mice; activity and urinary orotic acid over lifespan

    PMID:19384294

    Open questions at the time
    • Strategies to overcome dilution in neonates not solved
    • Integration-based persistence not tested
  10. 2013 Medium

    Showed that the spatial distribution of OTC activity across hepatocytes, not total activity, governs ammonia detoxification.

    Evidence Neonatal AAV-OTC with shRNA knockdown of endogenous OTC and ammonia challenge in spf-ash mice

    PMID:24108150

    Open questions at the time
    • Quantitative spatial threshold not defined in this study
    • Mechanism linking distribution to ammonia flux not detailed
  11. 2015 Medium

    Characterized splicing pathogenesis of the c.386G>A allele and revealed species-specific cryptic-site usage, with antisense oligonucleotides able to redirect splicing.

    Evidence RT-PCR, minigene assays in human and mouse hepatoma cells, ASO treatment, activity assay

    PMID:25853564

    Open questions at the time
    • Trans-acting splicing factor not yet identified at this stage
    • Therapeutic efficacy in vivo not demonstrated here
  12. 2017 Low

    Extended OTC's functional reach to the brain by localizing the protein to a subset of nNOS-positive neurons, implying support of neuronal NO synthesis.

    Evidence Double immunolabeling immunocytochemistry for OTC and nNOS in human brain sections

    PMID:28868581

    Open questions at the time
    • Single immunolocalization method without functional perturbation
    • Functional contribution of neuronal OTC to NO not directly measured
  13. 2018 Medium

    Quantified a cellular threshold for hepatic OTC function, linking X-inactivation skewing to OTC-positive hepatocyte fraction and metabolic stability.

    Evidence DNA methylation-based X-inactivation assay and high-resolution immunohistochemistry on explanted carrier livers

    PMID:29623395

    Open questions at the time
    • Threshold derived from limited number of explanted livers
    • Dynamics of the threshold under acute metabolic stress not captured
  14. 2021 Medium

    Identified the TIA1 splicing factor as the species-specific determinant of c.386G>A aberrant splicing and showed common polymorphisms modulate enzyme activity and can rescue pathogenic alleles in cis.

    Evidence RNA pulldown, minigene rescue, TIA1/U1snRNA manipulation; in vitro enzymatic assays of recombinant haplotype variants with structural analysis

    PMID:34015158 PMID:34906067

    Open questions at the time
    • Generalizability of TIA1-dependence to other OTC splicing variants unknown
    • Clinical penetrance modification by polymorphisms not established
  15. 2022 Medium

    Confirmed that a promoter variant in a conserved HNF4α site reduces transcription and is sufficient to cause late-onset hyperammonemia, defining the regulatory axis of OTC expression.

    Evidence Dual-luciferase reporter assays with promoter and promoter+enhancer constructs plus family segregation

    PMID:35605046

    Open questions at the time
    • Direct demonstration of altered HNF4α binding not shown
    • In vivo expression quantification absent
  16. 2023 High

    Delivered a near-saturation functional map of OTC missense variants, distinguishing benign from pathogenic alleles, correlating with onset severity, and defining a structural domain (SMG loop) essential for activity.

    Evidence High-throughput yeast functional complementation / deep mutational scanning of 1,570 variants with clinical and structural correlation

    PMID:37146589

    Open questions at the time
    • Yeast assay does not capture mammalian mitochondrial import effects fully
    • SMG loop role required in human cells but not yeast suggests context-dependence not fully explained
  17. 2020 Medium

    Provided in vivo proof-of-principle that engineered exon-specific U1snRNA can correct an OTC splicing defect and restore protein expression.

    Evidence AAV8 hepatocyte delivery of ExSpeU1O3 in spf-ash mice; RT-PCR splicing analysis, Western blot, immunostaining

    PMID:33228018

    Open questions at the time
    • Correction only partial (6.1% to 17.2% correct transcript)
    • Durability and metabolic correction in disease challenge not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • How OTC enzyme activity is distributed and regulated across hepatocytes in human carriers in real time, and whether neuronal OTC functionally contributes to brain NO signaling, remain unresolved.
  • No dynamic single-cell measure of human hepatic OTC activity distribution
  • No functional perturbation of neuronal OTC
  • Mechanism of human precursor mitochondrial import block still unexplained

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 5 GO:0016874 ligase activity 2
Localization
GO:0005739 mitochondrion 2
Pathway
R-HSA-1430728 Metabolism 3 R-HSA-74160 Gene expression (Transcription) 2

Evidence

Reading pass · 26 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1991 Rat OTC cDNA under a liver/intestinal promoter (1.3 kb 5' flanking region of rat OTC gene) corrects both hepatic and small intestinal OTC activity in OTC-deficient spf-ash mice, demonstrating that the transgene product is enzymatically functional in vivo and that small intestinal OTC contributes to orotic acid excretion. Transgenic mouse rescue; enzymatic activity assay; urinary orotic acid measurement FEBS letters Medium 2001730
1991 In heterozygous female OTC-deficient spf-ash mice, the proportion of hepatocytes expressing normal OTC protein (assessed by anti-OTC immunofluorescence and enzymatic activity) is directly correlated with liver OTC activity, demonstrating that X-chromosome inactivation mosaicism in hepatocytes is the primary determinant of residual OTC enzymatic output in carrier livers. Immunofluorescence microscopy with anti-OTC antibody; radiochromatographic enzymatic activity assay; quantitative morphometry Biochemical medicine and metabolic biology Medium 2049185
1991 In cell fusion experiments, the silent OTC gene of BWTG3 hepatoma cells could be reactivated only by fusion with OTC+ hepatocytes, not by hormone treatment or azacytidine, indicating that OTC gene activation requires trans-acting hepatocyte-specific factors beyond simple demethylation; the reactivated gene produced enzyme with a pH-dependence characteristic of the hepatoma-derived (wild-type) OTC. Cell fusion; enzymatic activity assay; pH-dependence characterization of enzyme product Journal of cell science Medium 1860901
1993 Missense mutations S192R, D196V, T264A, M268T, and R277W in the OTC protein coding region cause OTC deficiency; mutations in exons encoding the active site or core domain resulted in neonatal-onset disease, while surface mutations were associated with late-onset, supporting that core structural/catalytic residues are required for full OTC activity. PCR-SSCP; DNA sequencing; genotype-phenotype correlation across patients Human genetics Low 8365726
1993 Zinc supplementation in cirrhotic rats increases liver OTC enzymatic activity in a manner positively correlated with hepatic zinc content, demonstrating that zinc modulates OTC enzymatic activity in vivo. Oral zinc supplementation in CCl4-cirrhotic rat model; liver OTC activity assay; serum and hepatic zinc measurement Journal of trace elements and electrolytes in health and disease Low 8019156
1995 Small intestinal OTC activity is more important than hepatic OTC activity for controlling urinary orotic acid excretion in spf-ash mice; transgenic restoration of intestinal OTC to ~30% of control prevented excessive orotic aciduria, whereas hepatic OTC at ~10% was insufficient. Transgenic spf-ash mice with tissue-specific OTC expression; urinary orotic acid measurement; hepatic and intestinal OTC activity assay Biochimica et biophysica acta Medium 7827141
1996 Adenoviral vector expressing human OTC cDNA under the CAG promoter restored hepatic OTC enzyme activity to normal levels and normalized urinary orotic acid in adult spf-ash mice, and produced 10–40-fold higher OTC enzyme activity in OTC-deficient human primary hepatocytes compared to an SR-alpha promoter vector, establishing that promoter strength critically determines correction of enzymatic activity. Recombinant adenoviral gene delivery; OTC enzymatic activity assay; Western blot; urinary orotic acid measurement Human gene therapy Medium 8860834
1997 Mutations P225L and P225R in the OTC gene are associated with undetectable OTC antigen in liver homogenates and near-complete loss of enzyme activity; the residual P225L mutant enzyme has normal pH dependence, normal Km values for ornithine and carbamoyl phosphate, and normal stability, suggesting that the dramatic reduction in protein level results from degradation of the mutant precursor during mitochondrial import rather than from a catalytic defect. Liver OTC antigen quantification (Western blot); OTC enzymatic activity assay; pH and Km kinetic analysis; thermal stability assay Journal of inherited metabolic disease Medium 9427144
1997 Transfection of COS1 cells with OTC cDNA carrying the L148F mutation produced undetectable enzyme activity, confirming this missense mutation as pathogenic by in vitro expression. Transient transfection of COS1 cells with mutant OTC cDNA; enzymatic activity assay American journal of medical genetics Low 9056557
1999 Adenoviral delivery of mouse OTC cDNA to spf-ash mice resulted in efficient mitochondrial import of newly synthesized OTC protein; in contrast, human OTC showed accumulation of precursor in the cytosol, suggesting a species-specific block in mitochondrial translocation. Correction of hepatic OTC activity also normalized the secondary reduction in mitochondrial ATPase subunit c and partially corrected elevated CPS-I levels. Electron microscope immunolocalization; quantitative morphometry; liver OTC activity assay; subcellular fractionation Molecular medicine (Cambridge, Mass.) Medium 10448647
2006 Ornithine supplementation in Otc(spf-ash) mice restores ureagenesis rate, reduces plasma ammonia, and normalizes transfer of 15N from glutamine to urea; these effects demonstrate that ornithine substrate availability is rate-limiting for OTC function in the partially deficient state. Multiple stable isotope tracer infusion protocol; urea kinetics; plasma amino acid and ammonia measurement in conscious mice The Journal of nutrition Medium 16772445
2006 Despite only ~5–7% residual OTC activity, Otc(spf-ash) mice sustain normal ureagenesis when supplied a balanced complete amino acid mixture, demonstrating that substrate balance, not just OTC activity level, governs urea production capacity. Stable isotope tracer (15N15N urea) infusion for urea entry rate; plasma urea and ammonia measurement in conscious mice The Journal of nutrition Medium 16549467
2007 OTC protein structure analysis was used to predict whether missense mutations are disease-causing; mutations at the active site or in the core domain were consistently associated with complete deficiency, while surface mutations were associated with partial deficiency, validating the OTC crystal structure as a tool to interpret the functional impact of mutations. Structure-based analysis of OTC crystal structure; genotype-phenotype correlation; comparison with in silico prediction tools Journal of inherited metabolic disease Low 17334707
2008 OTC deficiency in spf-ash mice reduces systemic citrulline production to 30–50% of controls, decreases de novo arginine synthesis, and reduces whole-body nitric oxide (NO) production by ~50% under basal conditions; after LPS-induced net protein breakdown increases arginine availability, NO production is no longer impaired by OTC deficiency, demonstrating that OTC activity supports NO production via the citrulline–arginine pathway. Stable isotope tracers (LC-MS); in vivo NO production measured as conversion of [15N2]arginine to [15N]citrulline; de novo arginine production measured as [13C/2H]citrulline to [13C/2H]arginine conversion American journal of physiology. Endocrinology and metabolism High 18697914
2009 AAV2/8-mediated delivery of murine OTC cDNA to adult spf-ash mice achieved supraphysiological hepatic OTC enzyme activity and robust, life-long metabolic correction (normalized urinary orotic acid); in neonatal mice, metabolic correction was transient due to hepatocellular proliferation diluting episomal vector genomes, demonstrating that hepatocellular division is a specific barrier to sustained OTC gene therapy. AAV vector delivery; OTC enzymatic activity assay; urinary orotic acid metabolic correction measurement; liver histology Molecular therapy : the journal of the American Society of Gene Therapy Medium 19384294
2010 A single nucleotide substitution c.-366A>G upstream of the OTC transcription start site does not alter the promoter's intrinsic function alone but disrupts the interaction between the OTC promoter and an upstream enhancer element, reducing OTC transcriptional activity and contributing to liver-specific expression; this establishes that full OTC expression requires promoter-enhancer cooperation. Dual luciferase reporter assay; transcription start site mapping; promoter and enhancer functional analysis Human mutation Medium 20127982
2013 In spf-ash mice that received neonatal AAV-OTC therapy, vector-encoded OTC activity persisting to adulthood (up to 33% of wild-type) was insufficient to protect against hyperammonemia when endogenous OTC was knocked down by shRNA, demonstrating that the distribution of OTC activity across hepatocytes—not just total activity level—is critical for ammonia detoxification. AAV gene delivery in neonates; shRNA knockdown of residual OTC; ammonia challenge; vector genome quantification by qPCR Gene therapy Medium 24108150
2015 The c.386G>A (p.R129H) OTC mutation at the last nucleotide of exon 4 disrupts the 5' splice site and activates a cryptic splice site, but the specific cryptic site used differs between mouse (48 bp into intron 4) and human (4 bp into intron 4, or exon 4 skipping), resulting in species-specific transcript profiles and residual OTC enzyme activities of 3–6% in both; antisense oligonucleotides blocking the murine cryptic site partially redirect splicing toward the natural site. RT-PCR of liver tissue; minigene splicing assay in human and mouse hepatoma cells; antisense oligonucleotide treatment; OTC enzymatic activity assay PloS one Medium 25853564
2017 OTC protein expression was detected by immunocytochemistry in a small subset of nitrergic (nNOS-positive) neurons in human brain, and double immunolabeling showed co-localization with nNOS, suggesting that OTC-derived citrulline supports arginine availability and thus NO production specifically in these neurons. Double immunolabeling immunocytochemistry for OTC and nNOS in human brain sections Metabolic brain disease Low 28868581
2018 In explanted livers from heterozygous OTC-deficient females, intra-hepatic X-inactivation ratios (favoring the mutant allele) assessed by DNA methylation assay correlated directly with the proportion of OTC-immunopositive hepatocytes on high-resolution immunohistochemical analysis; approximately 20–30% of OTC-expressing hepatocytes was insufficient to maintain metabolic stability, establishing a cellular threshold for OTC function in the liver. DNA methylation-based X-inactivation assay; high-resolution immunohistochemical quantification of OTC-positive hepatocytes on >5 cm2 liver area Virchows Archiv : an international journal of pathology Medium 29623395
2021 Species-specific intronic nucleotides at positions +10–11 downstream of exon 4 govern TIA1 splicing factor binding; in the mouse context the +10–11 sequence confers preferential TIA1 binding (shown by RNA pulldown), and TIA1 overexpression increases correct splicing. Swapping human +10–11 nucleotides into the mouse context abolished TIA1-mediated splicing rescue and responsiveness to compensatory U1snRNA, explaining why the c.386G>A OTC mutation produces different aberrant transcripts in mice versus humans. RNA pulldown assay for TIA1 binding; minigene splicing assay in human and mouse hepatoma cells; TIA1 overexpression; engineered U1snRNA co-expression Molecular medicine (Cambridge, Mass.) Medium 34906067
2021 Common polymorphic OTC variants p.Lys46Arg and p.Gln270Arg modulate OTC enzymatic activity; the minor allele of p.Gln270Arg increases enzyme activity in the wild-type background and partially rescues activity when combined in cis with the pathogenic p.Arg40His mutation, as validated by in vitro enzymatic assays and structural analysis. In vitro OTC enzymatic assay of recombinant proteins with distinct haplotype combinations; structural analysis Human mutation Medium 34015158
2022 An OTC promoter variant c.-106C>A in a conserved HNF4α binding site reduces OTC promoter activity >5-fold in a dual-luciferase reporter assay; addition of the upstream OTC enhancer increases both wild-type and mutant promoter activity >5-fold but the mutant remains ~4-fold lower than wild-type, demonstrating that this promoter variant impairs OTC transcription and is sufficient to cause late-onset hyperammonemia under metabolic stress. Dual-luciferase reporter assay with isolated promoter and promoter+enhancer constructs; family segregation analysis Journal of inherited metabolic disease Medium 35605046
2023 A high-throughput functional assay measuring OTC activity in yeast expressing individual human OTC variants quantified the impact of 1,570 missense substitutions (84% of all SNV-accessible missense mutations); results distinguished known benign from pathogenic variants, correlated neonatal-onset from late-onset phenotypes, identified a 13-amino-acid 'SMG loop' required for OTC activity in human cells but not yeast, and showed that variants with complete loss of activity reclassify as likely pathogenic under ACMG criteria. High-throughput yeast-based functional complementation assay; deep mutational scanning; comparison with clinical classifications; protein structure analysis American journal of human genetics High 37146589
2020 AAV8-mediated delivery of an exon-specific U1snRNA (ExSpeU1O3) targeting an intronic region downstream of the defective exon 4 in spf-ash mice increased the proportion of correctly spliced OTC transcripts (from 6.1% to 17.2%) and increased OTC protein expression ~3-fold in hepatocytes, providing proof-of-principle that engineered U1snRNA can rescue a specific OTC splicing defect in vivo. AAV8 hepatocyte delivery; RT-PCR splicing analysis; Western blot; immunostaining International journal of molecular sciences Medium 33228018
1980 OTC in peripheral white blood cells has Km values for ornithine and carbamoyl phosphate (~6.4 mM and ~0.6 mM, respectively) that differ substantially from human liver OTC Km values (~0.6 mM and ~0.12 mM), indicating tissue-specific kinetic properties; lymphoid cell lines showed no detectable OTC activity regardless of arginine withdrawal. Radiochemical OTC activity assay with labeled carbamoyl phosphate substrate; Km determination; lymphoid cell culture Pediatric research Low 7208155

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Mutations and polymorphisms in the human ornithine transcarbamylase (OTC) gene. Human mutation 139 16786505
2009 AAV2/8-mediated correction of OTC deficiency is robust in adult but not neonatal Spf(ash) mice. Molecular therapy : the journal of the American Society of Gene Therapy 100 19384294
2020 Degradation of tetracycline antibiotics by Arthrobacter nicotianae OTC-16. Journal of hazardous materials 83 33265032
2012 Changes in the nitrogen removal performance and the properties of granular sludge in an Anammox system under oxytetracycline (OTC) stress. Bioresource technology 53 23232224
1996 Correction of ornithine transcarbamylase deficiency in adult spf(ash) mice and in OTC-deficient human hepatocytes with recombinant adenoviruses bearing the CAG promoter. Human gene therapy 53 8860834
1985 Gene for OTC: characterisation and linkage to Duchenne muscular dystrophy. Nucleic acids research 51 3839070
1988 Analysis of linkage relationships of X-linked retinitis pigmentosa with the following Xp loci: L1.28, OTC, 754, XJ-1.1, pERT87, and C7. Human genetics 50 3422211
2009 High-frequency detection of deletions and variable rearrangements at the ornithine transcarbamylase (OTC) locus by oligonucleotide array CGH. Molecular genetics and metabolism 45 19138872
2019 Therapeutic Role of a Cysteine Precursor, OTC, in Ischemic Stroke Is Mediated by Improved Proteostasis in Mice. Translational stroke research 44 31049841
1993 Four novel gene mutations in five Japanese male patients with neonatal or late onset OTC deficiency: application of PCR-single-strand conformation polymorphisms for all exons and adjacent introns [corrected]. Human genetics 44 8365726
2016 Frequency and Pathophysiology of Acute Liver Failure in Ornithine Transcarbamylase Deficiency (OTCD). PloS one 42 27070778
2017 AAV gene therapy corrects OTC deficiency and prevents liver fibrosis in aged OTC-knock out heterozygous mice. Molecular genetics and metabolism 41 28283349
2011 Preclinical evaluation of a clinical candidate AAV8 vector for ornithine transcarbamylase (OTC) deficiency reveals functional enzyme from each persisting vector genome. Molecular genetics and metabolism 40 22133298
1994 Sequences of the oxytetracycline polyketide synthase-encoding otc genes from Streptomyces rimosus. Gene 40 8163168
2009 Adult-onset ornithine transcarbamylase (OTC) deficiency unmasked by the Atkins' diet. Journal of hepatology 39 20031247
2015 Clinical outcomes and the mutation spectrum of the OTC gene in patients with ornithine transcarbamylase deficiency. Journal of human genetics 38 25994866
2007 Estimation of the total number of disease-causing mutations in ornithine transcarbamylase (OTC) deficiency. Value of the OTC structure in predicting a mutation pathogenic potential. Journal of inherited metabolic disease 37 17334707
2019 Action of oxytetracycline (OTC) degrading bacterium and its application in Moving Bed Biofilm Reactor (MBBR) for aquaculture wastewater pre-treatment. Ecotoxicology and environmental safety 35 30660977
2014 Sudden unexpected fatal encephalopathy in adults with OTC gene mutations-Clues for early diagnosis and timely treatment. Orphanet journal of rare diseases 35 25026867
2011 Sustained correction of OTC deficiency in spf( ash) mice using optimized self-complementary AAV2/8 vectors. Gene therapy 35 21850052
2007 Mutation analysis of the ornithine transcarbamylase (OTC) gene in five Japanese OTC deficiency patients revealed two known and three novel mutations including a deep intronic mutation. The Kobe journal of medical sciences 35 18204299
1990 The risks and benefits of an Rx-to-OTC switch. The case of over-the-counter H2-blockers. Medical care 34 1976142
2008 Analysis of mRNA transcripts improves the success rate of molecular genetic testing in OTC deficiency. Molecular genetics and metabolism 32 18440262
2005 PPI use in the OTC era: who to treat, with what, and for how long? Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association 29 15765438
2020 The otc gene of Streptococcus suis plays an important role in biofilm formation, adhesion, and virulence in a murine model. Veterinary microbiology 28 33181436
2013 Treatment with the cysteine precursor l-2-oxothiazolidine-4-carboxylate (OTC) implicates taurine deficiency in severity of dystropathology in mdx mice. The international journal of biochemistry & cell biology 28 23892094
1999 The effect of an Rx-to-OTC switch on medication prescribing patterns and utilization of physician services: the case of H2-receptor antagonists. Medical care 27 10213023
1997 The ornithine transcarbamylase (OTC) gene: mutations in 50 Japanese families with OTC deficiency. American journal of medical genetics 26 9286441
2019 Efficient in vivo editing of OTC-deficient patient-derived primary human hepatocytes. JHEP reports : innovation in hepatology 25 32039406
2015 Functional characterization of the spf/ash splicing variation in OTC deficiency of mice and man. PloS one 22 25853564
1996 Asymptomatic and late-onset ornithine transcarbamylase (OTC) deficiency in males of a five-generation family, caused by an A208T mutation. Clinical genetics 22 9007316
2023 Simultaneous adsorption of Cd(II) and degradation of OTC by activated biochar with ferrate: Efficiency and mechanism. Journal of hazardous materials 21 36641845
2015 Oculo-facio-cardio-dental (OFCD) syndrome: the first Italian case of BCOR and co-occurring OTC gene deletion. Gene 21 25620158
2013 Multidisciplinary management of ornithine transcarbamylase (OTC) deficiency in pregnancy: essential to prevent hyperammonemic complications. BMJ case reports 21 23283608
2017 A Proposed Physiopathological Pathway to Hyperammonemic Encephalopathy in a Non-Cirrhotic Patient with Fibrolamellar Hepatocellular Carcinoma without Ornithine Transcarbamylase (OTC) Mutation. The American journal of case reports 20 28270654
2023 The functional impact of 1,570 individual amino acid substitutions in human OTC. American journal of human genetics 19 37146589
2013 AAV-encoded OTC activity persisting to adulthood following delivery to newborn spf(ash) mice is insufficient to prevent shRNA-induced hyperammonaemia. Gene therapy 18 24108150
2009 Molecular mechanisms underlying large genomic deletions in ornithine transcarbamylase (OTC) gene. Clinical genetics 18 19475717
1997 Familial lethal inheritance of a mutated paternal gene in females causing X-linked ornithine transcarbamylase (OTC) deficiency. American journal of medical genetics 18 9056557
2021 OTC deficiency in females: Phenotype-genotype correlation based on a 130-family cohort. Journal of inherited metabolic disease 17 34014569
2012 Plant growth stimulation in Prunus species plantlets by BTH or OTC treatments under in vitro conditions. Journal of plant physiology 17 22595304
1993 Effects of zinc on hepatic ornithine transcarbamylase (OTC) activity. Journal of trace elements and electrolytes in health and disease 17 8019156
2002 Identification of seven novel missense mutations, two splice-site mutations, two microdeletions and a polymorphic amino acid substitution in the gene for ornithine transcarbamylase (OTC) in patients with OTC deficiency. Human mutation 16 11793483
2018 Variable X-chromosome inactivation and enlargement of pericentral glutamine synthetase zones in the liver of heterozygous females with OTC deficiency. Virchows Archiv : an international journal of pathology 15 29623395
2008 Postchemotherapy hyperammonemic encephalopathy emulating ornithine transcarbamoylase (OTC) deficiency. Southern medical journal 15 18414167
2008 Reduced citrulline availability by OTC deficiency in mice is related to reduced nitric oxide production. American journal of physiology. Endocrinology and metabolism 15 18697914
2000 Lymphocyte mRNA analysis of the ornithine transcarbamylase gene in Italian OTCD male patients and manifesting carriers: identification of novel mutations. Human mutation 15 10737985
2021 Genomic insights into the antibiotic resistance pattern of the tetracycline-degrading bacterium, Arthrobacter nicotianae OTC-16. Scientific reports 14 34341372
2006 Identification of novel mutations in the human ornithine transcarbamylase (OTC) gene of Korean patients with OTC deficiency and transient expression of the mutant proteins in vitro. Human mutation 14 17041896
2002 Genetic analysis in nine unrelated Italian patients affected by OTC deficiency: detection of novel mutations in the OTC gene. Molecular genetics and metabolism 14 12083811
1976 Propionic acidemia and hyperlysinemia in a case with ornithine transcarbamylase (OTC) deficiency. The Journal of clinical endocrinology and metabolism 14 977722
1998 Selective elevation of glutathione levels in target tissues with L-2-oxothiazolidine-4-carboxylate (OTC) protects against hyperoxia-induced lung damage in protein-energy malnourished rats: implications for a new treatment strategy. The Journal of nutrition 13 9521626
1991 Correction of ornithine transcarbamylase (OTC) deficiency in spf-ash mice by introduction of rat OTC gene. FEBS letters 12 2001730
1986 Clinical application of DNA analysis in a family with OTC deficiency. American journal of medical genetics 12 2878615
2020 An Exon-Specific Small Nuclear U1 RNA (ExSpeU1) Improves Hepatic OTC Expression in a Splicing-Defective spf/ash Mouse Model of Ornithine Transcarbamylase Deficiency. International journal of molecular sciences 11 33228018
2016 Performance and microbial community variations in thermophilic anaerobic digesters treating OTC medicated cow manure under different operational conditions. Bioresource technology 11 26826959
2010 Disruption of OTC promoter-enhancer interaction in a patient with symptoms of ornithine carbamoyltransferase deficiency. Human mutation 11 20127982
2006 Ornithine restores ureagenesis capacity and mitigates hyperammonemia in Otc(spf-ash) mice. The Journal of nutrition 11 16772445
2017 Activity of the liver enzyme ornithine carbamoyltransferase (OTC) in blood: LC-MS/MS assay for non-invasive diagnosis of ornithine carbamoyltransferase deficiency. Clinical chemistry and laboratory medicine 10 28107167
1999 Identification of a cytogenetic deletion and of four novel mutations (Q69X, I172F, G188V, G197R) affecting the gene for ornithine transcarbamylase (OTC) in Spanish patients with OTC deficiency. Human mutation 10 10502831
1996 Identification of new mutations in the ornithine transcarbamylase (OTC) gene in Korean families. Journal of inherited metabolic disease 10 8830175
2021 Alert to US physicians: DHEA, widely used as an OTC androgen supplement, may exacerbate COVID-19. Endocrine-related cancer 9 33263566
2021 A deep intronic variant is a common cause of OTC deficiency in individuals with previously negative genetic testing. Molecular genetics and metabolism reports 9 33489762
2006 Reduced ornithine transcarbamylase activity does not impair ureagenesis in Otc(spf-ash) mice. The Journal of nutrition 9 16549467
1999 Efficient mitochondrial import of newly synthesized ornithine transcarbamylase (OTC) and correction of secondary metabolic alterations in spf(ash) mice following gene therapy of OTC deficiency. Molecular medicine (Cambridge, Mass.) 9 10448647
1999 Influence of experimentally induced theileriosis (Theileria annulata) on the pharmacokinetics of a long-acting formulation of oxytetracycline (OTC-LA) in calves. Journal of veterinary pharmacology and therapeutics 9 10597536
2024 Are asymptomatic carriers of OTC deficiency always asymptomatic? A multicentric retrospective study of risk using the UCDC longitudinal study database. Molecular genetics & genomic medicine 8 38634223
2020 Late-Onset Ornithine Transcarbamylase Deficiency and Variable Phenotypes in Vietnamese Females With OTC Mutations. Frontiers in pediatrics 8 32793520
2014 OTC gene in ornithine transcarbamylase deficiency: clinical course and mutational spectrum in seven Korean patients. Pediatric neurology 8 25011434
1989 Structure of the ornithine transcarbamylase (OTC) gene and DNA diagnosis of OTC deficiency. Clinica chimica acta; international journal of clinical chemistry 8 2575934
2022 A promoter variant in the OTC gene associated with late and variable age of onset hyperammonemia. Journal of inherited metabolic disease 7 35605046
2021 Common polymorphic OTC variants can act as genetic modifiers of enzymatic activity. Human mutation 7 34015158
1997 Missense mutations in codon 225 of ornithine transcarbamylase (OTC) result in decreased amounts of OTC protein: a hypothesis on the molecular mechanism of the OTC deficiency. Journal of inherited metabolic disease 7 9427144
1996 Prenatal monitoring in a family at high risk for ornithine transcarbamylase (OTC) deficiency: a new mutation of an A-to-C transversion in position +4 of intron 1 of the OTC gene that is likely to abolish enzyme activity. American journal of medical genetics 7 8862622
1988 The pharmacological profile of non-opioid (OTC) analgesics: aspirin, paracetamol (acetaminophen), ibuprofen, and phenazones. Agents and actions. Supplements 7 3066205
2023 Plasma-Polymerised Antibacterial Coating of Ovine Tendon Collagen Type I (OTC) Crosslinked with Genipin (GNP) and Dehydrothermal-Crosslinked (DHT) as a Cutaneous Substitute for Wound Healing. Materials (Basel, Switzerland) 6 37049037
2017 In human brain ornithine transcarbamylase (OTC) immunoreactivity is strongly expressed in a small number of nitrergic neurons. Metabolic brain disease 6 28868581
2006 The efficacy of hydrotalcite compared with OTC famotidine in the on-demand treatment of gastroesophageal reflux disease: a non-inferiority trial. Medical science monitor : international medical journal of experimental and clinical research 6 17179910
1995 Importance of ornithine transcarbamylase (OTC) deficiency in small intestine for urinary orotic acid excretion: analysis of OTC-deficient spf-ash mice with OTC transgene. Biochimica et biophysica acta 6 7827141
1991 X-chromosome inactivation in the liver of female heterozygous OTC-deficient sparse-furash mice. Biochemical medicine and metabolic biology 6 2049185
2023 Monitoring of over-the-counter (OTC) and COVID-19 treatment drugs complement wastewater surveillance of SARS-CoV-2. Journal of exposure science & environmental epidemiology 5 38052940
2021 Generation of a human induced pluripotent stem cell line (SDQLCHi036-A) from a patient with ornithine transcarbamylase deficiency carrying a deletion involving 3-9 exons of OTC gene. Stem cell research 5 33550136
2021 OTC intron 4 variations mediate pathogenic splicing patterns caused by the c.386G>A mutation in humans and spfash mice, and govern susceptibility to RNA-based therapies. Molecular medicine (Cambridge, Mass.) 5 34906067
2009 Mutation screening of the medium-chain acyl-CoA dehydrogenase (MCAD) and the ornithine transcarbamylase (OTC) genes by multiplex PCR amplification and sequencing. Clinical chemistry and laboratory medicine 5 19055470
2006 Mutational spectrum and linkage disequilibrium patterns at the ornithine transcarbamylase gene (OTC). Annals of human genetics 5 17044854
2002 H intragenic polymorphisms and haplotype analysis in the ornithine transcarbamylase (OTC) gene and their relevance for tracking the inheritance of OTC deficiency. Human mutation 5 12402347
1991 BWTG3 hepatoma cells can acquire phenylalanine hydroxylase, cystathionine synthase and CPS-I without genetic manipulation, but activation of the silent OTC gene requires cell fusion with hepatocytes. Journal of cell science 5 1860901
1980 Ornithine transcarbamylase (OTC) in white blood cells. Pediatric research 5 7208155
2022 Effect of Ornithine Transcarbamylase (OTC) Deficiency on Pregnancy and Puerperium. Diagnostics (Basel, Switzerland) 4 35204506
2018 Gene Mutation Analysis and Prenatal Diagnosis of the Ornithine Transcarbamylase (OTC) Gene in Two Families with Ornithine Transcarbamylase Deficiency. Medical science monitor : international medical journal of experimental and clinical research 4 30333473
2017 Urea Cycle Defects: Early-Onset Disease Associated with A208T Mutation in OTC Gene-Expanding the Clinical Phenotype. Case reports in genetics 4 28261508
2016 Toxicity of OTC to Ipomoea aquatica Forsk. and to microorganisms in a long-term sewage-irrigated farmland soil. Environmental science and pollution research international 4 27083912
2014 Hyperammonemic coma in a patient with late-onset OTC deficiency. La Pediatria medica e chirurgica : Medical and surgical pediatrics 4 25573644
2012 Recurrent somnolence in a 17-month-old infant: late-onset ornithine transcarbamylase (OTC) deficiency due to the novel hemizygous mutation c.535C > T (p.Leu179Phe). European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society 4 22727265
2020 A novel splice site mutation in OTC gene of a female with ornithine transcarbamylase deficiency and her asymptomatic mosaic father. Journal of genetics 3 32482918
2018 Mutation Study of Malaysian Patients with Ornithine Transcarbamylase Deficiency: Clinical, Molecular, and Bioinformatics Analyses of Two Novel Missense Mutations of the OTC Gene. BioMed research international 3 30175132
2018 Exonic duplication of the OTC gene by a complex rearrangement that likely occurred via a replication-based mechanism: a case report. BMC medical genetics 3 30541480
2013 [Molecular diagnosis of OTC gene mutation in a Chinese family with ornithine transcarbamylase deficiency]. Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics 3 23568734
2005 Severe, neonatal-onset OTC deficiency in twin sisters with a de novo balanced reciprocal translocation t(X;5)(p21.1;q11). American journal of medical genetics. Part A 3 15578616
1995 OTC pharmaceuticals and genotoxicity testing: the paracetamol, anthraquinone, and griseofulvin cases. Archives of toxicology. Supplement. = Archiv fur Toxikologie. Supplement 3 7786168

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