{"gene":"DEGS1","run_date":"2026-04-28T17:46:02","timeline":{"discoveries":[{"year":1997,"finding":"DEGS1 (MLD gene product) is a member of the membrane fatty acid desaturase family, contains three consensus histidine-rich motifs (HX3H, HX2HH, HX2HHXFP) characteristic of membrane fatty acid desaturases, is extractable from particulate fractions only with detergent, and localizes to the endoplasmic reticulum. Overexpression inhibits biosynthesis of the EGF receptor without affecting PDGF receptor expression, suggesting a role in biosynthetic processing.","method":"Sequence analysis, subcellular fractionation, detergent/salt/urea extraction, immunolocalization to ER, cotransfection overexpression assay","journal":"Biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization experiment and functional consequence of overexpression, single lab","pmids":["9188692"],"is_preprint":false},{"year":2012,"finding":"DES1 (DEGS1) functions as a retinol isomerase (isomerase-2) in Müller glial cells of the retina; it coimmunoprecipitates with cellular retinaldehyde binding protein (CRALBP), purified DES1 has high isomerase-2 activity in the presence of appropriate cofactors, adenoviral DES1 gene therapy partially rescues biochemical and physiological phenotypes in Rpe65-/- mice, and RNAi knockdown reduces isomerase-2 activity in cultured Müller cells.","method":"Co-immunoprecipitation, in vitro isomerase assay with purified protein, RNAi knockdown, adenoviral gene therapy rescue in Rpe65-/- mice","journal":"Nature chemical biology","confidence":"High","confidence_rationale":"Tier 1-2 — purified protein in vitro activity, co-IP, genetic rescue, and RNAi phenotype, multiple orthogonal methods in one study","pmids":["23143414"],"is_preprint":false},{"year":2014,"finding":"DEGS1 is the desaturase catalyzing the last step in the main ceramide biosynthetic pathway (dihydroceramide to ceramide). Loss-of-function (pharmacological or genetic ablation) in preadipocytes prevents adipogenesis and decreases lipid accumulation, associated with elevated dihydroceramide content, oxidative stress, cell death, and cell cycle blockage. In vivo pharmacological inhibition of DEGS1 impairs adipocyte differentiation.","method":"Pharmacological inhibition, siRNA/genetic knockdown in preadipocytes, lipidomics, in vivo inhibitor treatment","journal":"Diabetes","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal loss-of-function approaches (pharmacological + genetic) with specific biochemical and cellular readouts","pmids":["25352638"],"is_preprint":false},{"year":2019,"finding":"DEGS1 catalyzes the conversion of dihydroceramide (DhCer) to ceramide (Cer) as the final step of de novo ceramide biosynthesis. Mutations in DEGS1 cause marked accumulation of dihydroceramide species and elevated DhCer/Cer ratios in patient fibroblasts and muscle, recapitulated in CRISPR/Cas9 DEGS1-knockout cells and by pharmacological inhibition. Patient fibroblast enzymatic activity was reduced by 80% vs. wild-type. A potentially neurotoxic atypical sphingosine isomer was identified in patient plasma and in cells expressing mutant DEGS1.","method":"Whole-exome sequencing, lipidomics in patient fibroblasts and plasma, CRISPR/Cas9 knockout cells, pharmacological inhibition, enzymatic activity assay","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1-2 — enzymatic activity measured directly in patient cells and KO cells, lipidomics orthogonally confirm substrate accumulation, replicated by two independent groups simultaneously","pmids":["30620337","30620338"],"is_preprint":false},{"year":2019,"finding":"DEGS1 encodes C4-dihydroceramide desaturase; missense variants cause accumulation of dihydroceramides, dihydrosphingosine, dihydrosphingosine-1-phosphate, and dihydrosphingomyelins with reduced ceramide, sphingosine, sphingosine-1-phosphate, and monohexosylceramides in patient blood, confirming the enzymatic role in ceramide synthesis pathway.","method":"Whole-exome sequencing, Sanger sequencing, lipidomics of whole blood","journal":"European journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 — lipidomics directly confirm substrate/product imbalance in patients, single lab","pmids":["31186544"],"is_preprint":false},{"year":2019,"finding":"A rare DEGS1 variant (L175Q) significantly reduces DEGS1 enzymatic activity; CRISPR/Cas9 editing of HepG2 cells confirmed partial loss of function, with heterozygotes showing dramatically reduced indexes of DEGS1 enzymatic activity and large increases in plasma dihydroceramides.","method":"CRISPR/Cas9 genome editing, plasma lipidomics, enzymatic activity assay","journal":"Journal of lipid research","confidence":"High","confidence_rationale":"Tier 1-2 — CRISPR-confirmed loss of function combined with enzymatic activity measurement and lipidomics","pmids":["31227640"],"is_preprint":false},{"year":2019,"finding":"Conditional knockout of Des1 in Müller cells of the retina (using Pdgfrα-Cre) causes no gross changes in retinal structure and no effect on cone sensitivity or dark adaptation, but slightly accelerates cone phototransduction termination rate. This indicates Des1 expression in Müller cells is not required for cone visual pigment regeneration in the mouse.","method":"Conditional knockout (Cre/lox), electrophysiology (ERG/single-cell recordings), tissue-selective gene recombination, Des1 catalytic activity assay","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 1-2 — clean conditional KO with functional electrophysiology readout and confirmed enzymatic activity reduction","pmids":["30645148"],"is_preprint":false},{"year":2011,"finding":"Myristic acid increases native DES1 (dihydroceramide Δ4-desaturase 1) enzymatic activity in cultured rat hepatocytes through N-myristoylation of the N-terminal glycine. The wild-type myristoylable form localizes to both ER and mitochondria, whereas a non-myristoylable mutant (N-terminal Gly→Ala) is almost exclusively in the ER, demonstrating that N-myristoylation targets a portion of DES1 from the ER to the mitochondrial outer membrane and increases ceramide levels and apoptosis.","method":"Site-directed mutagenesis (Gly→Ala), subcellular fractionation, organelle immunolocalization, enzymatic activity assay in hepatocytes and cell lysates","journal":"Lipids","confidence":"High","confidence_rationale":"Tier 1-2 — mutagenesis of modification site combined with subcellular fractionation and enzymatic activity assay","pmids":["22139871"],"is_preprint":false},{"year":2023,"finding":"DEGS1 is a mitochondria-associated endoplasmic reticulum membrane (MAM)-resident enzyme. DEGS1 deficiency disrupts core MAM functions: (a) mitochondrial dynamics — hyperfused mitochondrial network with decreased DRP1 activation; (b) cholesterol metabolism — impaired sterol O-acyltransferase activity and decreased cholesteryl esters; (c) phospholipid metabolism — increased phosphatidic acid and phosphatidylserine, decreased phosphatidylethanolamine; (d) lipid droplet biogenesis — increased size and numbers. Increased mitochondrial superoxide production and impaired mitochondrial respiration were also detected.","method":"Subcellular fractionation, multiomics (lipidomics, proteomics), enzymatic assays, patient fibroblasts, patient muscle biopsy, mitochondrial morphology imaging, superoxide measurement","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods (fractionation, enzymatic assays, multiomics, patient tissue) establishing MAM localization and downstream functional consequences","pmids":["36951944"],"is_preprint":false},{"year":2022,"finding":"DES1 (DEGS1) catalytic activity is necessary for anchorage-independent survival (AIS) in HER2+ cancer cells; DES1 acts downstream of HER2-driven glucose uptake and metabolism. Overexpression of DES1 is sufficient to drive AIS and in vitro tumorigenicity. DES1 functions as a transducer of HER2-driven glucose metabolic signals.","method":"Loss-of-function and gain-of-function (overexpression), anchorage-independent growth assay, epistasis with HER2 pathway","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2-3 — genetic loss/gain of function with defined cellular phenotype and pathway placement, single lab","pmids":["36165222"],"is_preprint":false},{"year":2023,"finding":"Two novel DEGS1 missense variants near the C-terminus are characterized; a structural model predicts the substrate-binding site. A regulatory link between DEGS1 and fatty acid desaturase 3 (FADS3) is proposed, as the atypical sphingoid base SPB 18:1(14Z);O2 — formed when DEGS1 is non-functional — is a specific biomarker for pathogenic DEGS1 variants.","method":"Structural modeling, plasma lipidomics (dihydrosphingolipids and atypical sphingoid base measurement), variant functional assessment","journal":"Journal of lipid research","confidence":"Medium","confidence_rationale":"Tier 3 — structural model and lipidomics biomarker; functional link is indirect, single lab","pmids":["37890668"],"is_preprint":false}],"current_model":"DEGS1 encodes dihydroceramide desaturase-1 (DES1), a multi-transmembrane endoplasmic reticulum/MAM-resident enzyme that introduces the Δ4-trans double bond into dihydroceramide to generate ceramide as the final step of de novo sphingolipid biosynthesis; its activity is enhanced by N-myristoylation (which also redirects a fraction to the mitochondrial outer membrane), it resides at the MAM where it maintains mitochondrial dynamics, cholesterol/phospholipid homeostasis, and lipid droplet biogenesis, it functions as a retinol isomerase in retinal Müller glia, and loss-of-function mutations cause pathological dihydroceramide accumulation leading to hypomyelinating leukodystrophy."},"narrative":{"teleology":[{"year":1997,"claim":"Establishing that DEGS1 is an ER-resident integral membrane protein of the fatty acid desaturase family provided the first molecular identity and predicted catalytic mechanism for the gene product.","evidence":"Sequence analysis, detergent extraction, and immunolocalization in transfected cells","pmids":["9188692"],"confidence":"Medium","gaps":["Enzymatic substrate and product not yet identified","Functional role of histidine motifs not mutagenetically confirmed","No lipid desaturase activity directly measured"]},{"year":2011,"claim":"Demonstrating that N-myristoylation of the N-terminal glycine enhances DES1 enzymatic activity and redirects the protein from the ER to the mitochondrial outer membrane revealed a post-translational regulatory mechanism controlling both enzyme activity and subcellular distribution.","evidence":"Site-directed mutagenesis (G→A), subcellular fractionation, and enzymatic activity assay in rat hepatocytes","pmids":["22139871"],"confidence":"High","gaps":["In vivo relevance of mitochondrial DES1 pool unknown","Whether myristoylation is regulated physiologically not addressed"]},{"year":2012,"claim":"Identifying DES1 as a retinol isomerase (isomerase-2) in Müller glia, with purified protein activity, co-IP with CRALBP, and partial rescue in Rpe65-/- mice, revealed an unexpected non-sphingolipid function for DEGS1.","evidence":"In vitro isomerase assay with purified DES1, co-immunoprecipitation, RNAi knockdown, adenoviral gene therapy in Rpe65-/- mice","pmids":["23143414"],"confidence":"High","gaps":["Conditional KO later showed Müller cell DES1 is dispensable for cone pigment regeneration in mouse (see 2019)","Whether isomerase activity is biologically relevant in human retina remains unresolved"]},{"year":2014,"claim":"Demonstrating that DEGS1 loss of function blocks adipogenesis with dihydroceramide accumulation, oxidative stress, and cell death established the enzyme as essential for the de novo ceramide biosynthesis pathway and linked its activity to cellular differentiation and survival.","evidence":"Pharmacological inhibition and siRNA knockdown in preadipocytes with lipidomics and in vivo inhibitor treatment","pmids":["25352638"],"confidence":"High","gaps":["Relative contribution of ceramide deficit vs. dihydroceramide accumulation not resolved","Mechanism linking sphingolipid imbalance to oxidative stress unclear"]},{"year":2019,"claim":"Identification of pathogenic DEGS1 mutations in patients with hypomyelinating leukodystrophy, confirmed by 80% reduction in enzymatic activity, dihydroceramide accumulation in patient cells, and recapitulation in CRISPR knockout cells, established DEGS1 as a Mendelian disease gene and demonstrated that a neurotoxic atypical sphingoid base is produced when the enzyme is defective.","evidence":"Whole-exome sequencing, patient fibroblast enzymatic assays, CRISPR/Cas9 KO cells, plasma and tissue lipidomics across two independent groups","pmids":["30620337","30620338","31186544","31227640"],"confidence":"High","gaps":["Mechanism by which atypical sphingoid base causes neurotoxicity not elucidated","Genotype-phenotype correlation across variant spectrum incomplete"]},{"year":2019,"claim":"Conditional knockout of Des1 in Müller cells showed no requirement for cone visual pigment regeneration, refining the earlier isomerase-2 finding and indicating functional redundancy or an alternative isomerase pathway in vivo.","evidence":"Conditional Cre/lox knockout in mouse Müller cells with ERG and single-cell electrophysiology","pmids":["30645148"],"confidence":"High","gaps":["Whether DES1 isomerase activity is relevant under pathological or aging conditions not tested","Compensation by other isomerases not investigated"]},{"year":2022,"claim":"Showing that DES1 catalytic activity is necessary and sufficient for anchorage-independent survival downstream of HER2-driven glucose metabolism placed the enzyme in an oncogenic signaling axis.","evidence":"Loss- and gain-of-function in HER2+ cancer cells, anchorage-independent growth assay, epistasis analysis","pmids":["36165222"],"confidence":"Medium","gaps":["In vivo tumorigenesis not tested","Mechanism connecting ceramide production to anchorage-independent survival unresolved","Single cancer cell type studied"]},{"year":2023,"claim":"Establishing DEGS1 as a MAM-resident enzyme whose deficiency disrupts mitochondrial dynamics, cholesterol/phospholipid metabolism, and lipid droplet biogenesis broadened the pathomechanism beyond sphingolipid imbalance to encompass global organelle-contact-site dysfunction.","evidence":"Subcellular fractionation, multi-omics, enzymatic assays, and mitochondrial imaging in patient fibroblasts and muscle biopsies","pmids":["36951944"],"confidence":"High","gaps":["Whether MAM dysfunction is a direct consequence of ceramide depletion or dihydroceramide accumulation not separated","Structural basis for DES1 enrichment at MAMs unknown"]},{"year":2023,"claim":"Structural modeling predicted the substrate-binding site and identified an atypical sphingoid base (SPB 18:1(14Z);O2) as a specific biomarker for pathogenic DEGS1 variants, suggesting a regulatory link with FADS3.","evidence":"Computational structural modeling and plasma lipidomics in patients with novel C-terminal variants","pmids":["37890668"],"confidence":"Medium","gaps":["No experimental structure available","FADS3 regulatory link not experimentally validated","Biomarker specificity not tested in large cohorts"]},{"year":null,"claim":"Key unresolved questions include the atomic structure of DES1, the mechanism by which dihydroceramide accumulation versus ceramide depletion each contribute to neuropathology, whether the neurotoxic atypical sphingoid base is a primary disease driver, and the physiological relevance of DES1 retinol isomerase activity in humans.","evidence":"","pmids":[],"confidence":"Low","gaps":["No crystal or cryo-EM structure","Neurotoxicity mechanism of atypical sphingoid base unknown","Relative pathogenic contribution of substrate accumulation vs. product deficit not separated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016491","term_label":"oxidoreductase activity","supporting_discovery_ids":[0,2,3,5,7,8]},{"term_id":"GO:0016853","term_label":"isomerase activity","supporting_discovery_ids":[1]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0,7,8]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[7,8]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[2,3,4,5,7,8]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[3,4,8]}],"complexes":[],"partners":["CRALBP","DRP1"],"other_free_text":[]},"mechanistic_narrative":"DEGS1 encodes dihydroceramide Δ4-desaturase 1 (DES1), the enzyme that catalyzes the final step of de novo sphingolipid biosynthesis by introducing a trans-double bond at the C4 position of dihydroceramide to generate ceramide [PMID:25352638, PMID:30620337]. The enzyme is an integral membrane protein of the endoplasmic reticulum and mitochondria-associated ER membranes (MAMs), containing conserved histidine-rich motifs characteristic of fatty acid desaturases; N-myristoylation of its N-terminal glycine enhances catalytic activity and redirects a fraction to the mitochondrial outer membrane [PMID:9188692, PMID:22139871, PMID:36951944]. DEGS1 deficiency disrupts MAM-dependent processes including mitochondrial dynamics (via impaired DRP1 activation), cholesterol esterification, phospholipid remodeling, and lipid droplet biogenesis, and also functions as a retinol isomerase in retinal Müller glial cells [PMID:36951944, PMID:23143414]. Loss-of-function mutations in DEGS1 cause pathological accumulation of dihydroceramides and generation of a neurotoxic atypical sphingoid base, resulting in hypomyelinating leukodystrophy [PMID:30620337, PMID:30620338]."},"prefetch_data":{"uniprot":{"accession":"O15121","full_name":"Sphingolipid delta(4)-desaturase DES1","aliases":["Cell migration-inducing gene 15 protein","Degenerative spermatocyte homolog 1","Dihydroceramide desaturase-1","Membrane lipid desaturase","Retinol isomerase"],"length_aa":323,"mass_kda":37.9,"function":"Has sphingolipid-delta-4-desaturase activity. Converts D-erythro-sphinganine to D-erythro-sphingosine (E-sphing-4-enine) (PubMed:11937514, PubMed:30620337, PubMed:30620338). Catalyzes the equilibrium isomerization of retinols (By similarity)","subcellular_location":"Mitochondrion membrane; Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/O15121/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/DEGS1","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000143753","cell_line_id":"CID000299","localizations":[{"compartment":"er","grade":3},{"compartment":"vesicles","grade":3}],"interactors":[{"gene":"SURF6","stoichiometry":0.2},{"gene":"EPS15L1","stoichiometry":0.2},{"gene":"CYP51A1","stoichiometry":0.2},{"gene":"POTEE","stoichiometry":0.2},{"gene":"VAPA","stoichiometry":0.2},{"gene":"VAPB","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000299","total_profiled":1310},"omim":[{"mim_id":"618404","title":"LEUKODYSTROPHY, HYPOMYELINATING, 18; HLD18","url":"https://www.omim.org/entry/618404"},{"mim_id":"615843","title":"DELTA(4)-DESATURASE, SPHINGOLIPID, 1; DEGS1","url":"https://www.omim.org/entry/615843"},{"mim_id":"610862","title":"DELTA(4)-DESATURASE, SPHINGOLIPID, 2; DEGS2","url":"https://www.omim.org/entry/610862"},{"mim_id":"312080","title":"PELIZAEUS-MERZBACHER DISEASE; PMD","url":"https://www.omim.org/entry/312080"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Mitochondria","reliability":"Supported"},{"location":"Plasma membrane","reliability":"Additional"},{"location":"Cytokinetic bridge","reliability":"Additional"},{"location":"Primary cilium","reliability":"Additional"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"skin 1","ntpm":505.2}],"url":"https://www.proteinatlas.org/search/DEGS1"},"hgnc":{"alias_symbol":["MLD","Des-1","DES1","FADS7","DEGS-1"],"prev_symbol":[]},"alphafold":{"accession":"O15121","domains":[{"cath_id":"-","chopping":"12-314","consensus_level":"high","plddt":97.7226,"start":12,"end":314}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O15121","model_url":"https://alphafold.ebi.ac.uk/files/AF-O15121-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O15121-F1-predicted_aligned_error_v6.png","plddt_mean":96.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=DEGS1","jax_strain_url":"https://www.jax.org/strain/search?query=DEGS1"},"sequence":{"accession":"O15121","fasta_url":"https://rest.uniprot.org/uniprotkb/O15121.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O15121/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O15121"}},"corpus_meta":[{"pmid":"12203137","id":"PMC_12203137","title":"Allogeneic mesenchymal stem cell infusion for treatment of metachromatic leukodystrophy (MLD) and Hurler syndrome (MPS-IH).","date":"2002","source":"Bone marrow transplantation","url":"https://pubmed.ncbi.nlm.nih.gov/12203137","citation_count":489,"is_preprint":false},{"pmid":"2539101","id":"PMC_2539101","title":"Insulin-like growth factor (IGF)-binding proteins inhibit the biological activities of IGF-1 and IGF-2 but not des-(1-3)-IGF-1.","date":"1989","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/2539101","citation_count":185,"is_preprint":false},{"pmid":"8095710","id":"PMC_8095710","title":"The nature of the trophic action of brain-derived neurotrophic factor, des(1-3)-insulin-like growth factor-1, and basic fibroblast growth factor on mesencephalic dopaminergic neurons developing in culture.","date":"1993","source":"Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/8095710","citation_count":172,"is_preprint":false},{"pmid":"1996625","id":"PMC_1996625","title":"IGF-I and the truncated analogue des-(1-3)IGF-I enhance growth in rats after gut resection.","date":"1991","source":"The American journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/1996625","citation_count":148,"is_preprint":false},{"pmid":"23143414","id":"PMC_23143414","title":"Identification of DES1 as a vitamin A isomerase in Müller glial cells of the retina.","date":"2012","source":"Nature chemical biology","url":"https://pubmed.ncbi.nlm.nih.gov/23143414","citation_count":91,"is_preprint":false},{"pmid":"2005410","id":"PMC_2005410","title":"Plasma clearance and tissue distribution of labelled insulin-like growth factor-I (IGF-I), IGF-II and des(1-3)IGF-I in rats.","date":"1991","source":"The Journal of endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/2005410","citation_count":86,"is_preprint":false},{"pmid":"30620337","id":"PMC_30620337","title":"Loss of the sphingolipid desaturase DEGS1 causes hypomyelinating leukodystrophy.","date":"2019","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/30620337","citation_count":79,"is_preprint":false},{"pmid":"30620338","id":"PMC_30620338","title":"DEGS1-associated aberrant sphingolipid metabolism impairs nervous system function in humans.","date":"2019","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/30620338","citation_count":79,"is_preprint":false},{"pmid":"8106515","id":"PMC_8106515","title":"Role of the NH2-terminal domain of angiotensin II (ANG II) and [Sar1]angiotensin II on conformation and activity. NMR evidence for aromatic ring clustering and peptide backbone folding compared with [des-1,2,3]angiotensin II.","date":"1994","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/8106515","citation_count":71,"is_preprint":false},{"pmid":"10702797","id":"PMC_10702797","title":"Cooperative interaction between mutant p53 and des(1-3)IGF-I accelerates mammary tumorigenesis.","date":"2000","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/10702797","citation_count":70,"is_preprint":false},{"pmid":"1710892","id":"PMC_1710892","title":"Increased weight gain, nitrogen retention and muscle protein synthesis following treatment of diabetic rats with insulin-like growth factor (IGF)-I and des(1-3)IGF-I.","date":"1991","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/1710892","citation_count":67,"is_preprint":false},{"pmid":"30119216","id":"PMC_30119216","title":"Withaferin-A attenuates multiple low doses of Streptozotocin (MLD-STZ) induced type 1 diabetes.","date":"2018","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/30119216","citation_count":63,"is_preprint":false},{"pmid":"1157223","id":"PMC_1157223","title":"Selective inhibition by des-1-Asp-8-lle-angiotensin ii of the steroidogenic response to restricted sodium intake in the rat.","date":"1975","source":"Circulation research","url":"https://pubmed.ncbi.nlm.nih.gov/1157223","citation_count":61,"is_preprint":false},{"pmid":"6194264","id":"PMC_6194264","title":"Myelin basic protein deposition in the optic and sciatic nerves of dysmyelinating mutants quaking, jimpy, Trembler, mld, and shiverer during development.","date":"1983","source":"Journal of neurochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/6194264","citation_count":59,"is_preprint":false},{"pmid":"6698966","id":"PMC_6698966","title":"Comparison of coagulation factor Xa and des-(1-44)factor Xa in the assembly of prothrombinase.","date":"1984","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/6698966","citation_count":59,"is_preprint":false},{"pmid":"1149185","id":"PMC_1149185","title":"Des-1-Asp-angiotensin II. Possible intrarenal role in homeostasis in the dog.","date":"1975","source":"Circulation research","url":"https://pubmed.ncbi.nlm.nih.gov/1149185","citation_count":58,"is_preprint":false},{"pmid":"25352638","id":"PMC_25352638","title":"Increased dihydroceramide/ceramide ratio mediated by defective expression of degs1 impairs adipocyte differentiation and function.","date":"2014","source":"Diabetes","url":"https://pubmed.ncbi.nlm.nih.gov/25352638","citation_count":56,"is_preprint":false},{"pmid":"1684088","id":"PMC_1684088","title":"Two new arylsulfatase A (ARSA) mutations in a juvenile metachromatic leukodystrophy (MLD) patient.","date":"1991","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/1684088","citation_count":55,"is_preprint":false},{"pmid":"1281142","id":"PMC_1281142","title":"des-(1-3)-IGF-I, an insulin-like growth factor analog used to mimic a potential IGF-II autocrine loop, promotes the differentiation of human colon-carcinoma cells.","date":"1992","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/1281142","citation_count":49,"is_preprint":false},{"pmid":"7988428","id":"PMC_7988428","title":"Generation of des-(1-3) insulin-like growth factor-I in serum by an acid protease.","date":"1994","source":"Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/7988428","citation_count":45,"is_preprint":false},{"pmid":"21831620","id":"PMC_21831620","title":"Prevention of multiple low-dose streptozotocin (MLD-STZ) diabetes in mice by an extract from gum resin of Boswellia serrata (BE).","date":"2011","source":"Phytomedicine : international journal of phytotherapy and phytopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/21831620","citation_count":44,"is_preprint":false},{"pmid":"9188692","id":"PMC_9188692","title":"The product of the MLD gene is a member of the membrane fatty acid desaturase family: overexpression of MLD inhibits EGF receptor biosynthesis.","date":"1997","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9188692","citation_count":38,"is_preprint":false},{"pmid":"31186544","id":"PMC_31186544","title":"DEGS1 variant causes neurological disorder.","date":"2019","source":"European journal of human genetics : EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/31186544","citation_count":37,"is_preprint":false},{"pmid":"2452084","id":"PMC_2452084","title":"Gene organization and transcription of duplicated MBP genes of myelin deficient (shi(mld)) mutant mouse.","date":"1988","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/2452084","citation_count":37,"is_preprint":false},{"pmid":"6202376","id":"PMC_6202376","title":"Myelination in the CNS of mld mutant mice: comparison between composition and structure.","date":"1984","source":"Brain research","url":"https://pubmed.ncbi.nlm.nih.gov/6202376","citation_count":37,"is_preprint":false},{"pmid":"1928375","id":"PMC_1928375","title":"IGF-I and its variant, des-(1-3)IGF-I, enhance growth in rats with reduced renal mass.","date":"1991","source":"The American journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/1928375","citation_count":35,"is_preprint":false},{"pmid":"36951944","id":"PMC_36951944","title":"Sphingolipid desaturase DEGS1 is essential for mitochondria-associated membrane integrity.","date":"2023","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/36951944","citation_count":34,"is_preprint":false},{"pmid":"1633884","id":"PMC_1633884","title":"Two different Ca2+ ion binding sites in factor VIIa and in des(1-38) factor VIIa.","date":"1992","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/1633884","citation_count":34,"is_preprint":false},{"pmid":"1388667","id":"PMC_1388667","title":"An evaluation of different enzymatic cleavage methods for recombinant fusion proteins, applied on des(1-3)insulin-like growth factor I.","date":"1992","source":"Journal of protein chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/1388667","citation_count":34,"is_preprint":false},{"pmid":"8930132","id":"PMC_8930132","title":"Des(1-3)IGF-I: a truncated form of insulin-like growth factor-I.","date":"1996","source":"The international journal of biochemistry & cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/8930132","citation_count":33,"is_preprint":false},{"pmid":"10682309","id":"PMC_10682309","title":"A non-glycosylated and functionally deficient mutant (N215H) of the sphingolipid activator protein B (SAP-B) in a novel case of metachromatic leukodystrophy (MLD).","date":"2000","source":"Journal of inherited metabolic disease","url":"https://pubmed.ncbi.nlm.nih.gov/10682309","citation_count":31,"is_preprint":false},{"pmid":"2440764","id":"PMC_2440764","title":"Structure and expression of myelin basic protein gene sequences in the mld mutant mouse: reiteration and rearrangement of the MBP gene.","date":"1987","source":"Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/2440764","citation_count":31,"is_preprint":false},{"pmid":"11250928","id":"PMC_11250928","title":"Inability of overexpressed des(1-3)human insulin-like growth factor I (IGF-I) to inhibit forced mammary gland involution is associated with decreased expression of IGF signaling molecules.","date":"2001","source":"Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/11250928","citation_count":27,"is_preprint":false},{"pmid":"24572788","id":"PMC_24572788","title":"Long-term correction of biochemical and neurological abnormalities in MLD mice model by neonatal systemic injection of an AAV serotype 9 vector.","date":"2014","source":"Gene therapy","url":"https://pubmed.ncbi.nlm.nih.gov/24572788","citation_count":27,"is_preprint":false},{"pmid":"1715381","id":"PMC_1715381","title":"The effects of insulin-like growth factor-I (IGF-I), IGF-II and des(1-3)IGF-I, a potent IGF analogue, on growth hormone and IGF-binding protein secretion from cultured rat anterior pituitary cells.","date":"1991","source":"The Journal of endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/1715381","citation_count":27,"is_preprint":false},{"pmid":"10048587","id":"PMC_10048587","title":"Effect of insulin-like growth factor (IGF)-I and Des (1-3) IGF-I on the level of IGF binding protein-3 and IGF binding protein-3 mRNA in cultured porcine embryonic muscle cells.","date":"1999","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/10048587","citation_count":26,"is_preprint":false},{"pmid":"33318877","id":"PMC_33318877","title":"The coordination of guard-cell autonomous ABA synthesis and DES1 function in situ regulates plant water deficit responses.","date":"2020","source":"Journal of advanced research","url":"https://pubmed.ncbi.nlm.nih.gov/33318877","citation_count":25,"is_preprint":false},{"pmid":"7779409","id":"PMC_7779409","title":"Des (1-3) IGF-I potently enhances differentiated cell growth in olfactory bulb organ culture.","date":"1994","source":"Growth factors (Chur, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/7779409","citation_count":25,"is_preprint":false},{"pmid":"30645148","id":"PMC_30645148","title":"Conditional deletion of Des1 in the mouse retina does not impair the visual cycle in cones.","date":"2019","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/30645148","citation_count":23,"is_preprint":false},{"pmid":"31227640","id":"PMC_31227640","title":"Rare DEGS1 variant significantly alters de novo ceramide synthesis pathway.","date":"2019","source":"Journal of lipid research","url":"https://pubmed.ncbi.nlm.nih.gov/31227640","citation_count":23,"is_preprint":false},{"pmid":"30498495","id":"PMC_30498495","title":"IL-33 Prevents MLD-STZ Induction of Diabetes and Attenuate Insulitis in Prediabetic NOD Mice.","date":"2018","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/30498495","citation_count":23,"is_preprint":false},{"pmid":"6680688","id":"PMC_6680688","title":"Intrinsic myelin proteins are normally synthesized in vitro in the myelin-deficient (mld) mutant mouse.","date":"1983","source":"Developmental neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/6680688","citation_count":23,"is_preprint":false},{"pmid":"7909611","id":"PMC_7909611","title":"The des(1-6)antennapedia homeodomain: comparison of the NMR solution structure and the DNA-binding affinity with the intact Antennapedia homeodomain.","date":"1994","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/7909611","citation_count":23,"is_preprint":false},{"pmid":"9007312","id":"PMC_9007312","title":"Late juvenile metachromatic leukodystrophy (MLD) in three patients with a similar clinical course and identical mutation on one allele.","date":"1996","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/9007312","citation_count":22,"is_preprint":false},{"pmid":"14517960","id":"PMC_14517960","title":"Identification of nine novel arylsulfatase a (ARSA) gene mutations in patients with metachromatic leukodystrophy (MLD).","date":"2003","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/14517960","citation_count":20,"is_preprint":false},{"pmid":"2443219","id":"PMC_2443219","title":"Immunohistochemical, biochemical and electron microscopic analysis of myelin formation in the central nervous system of myelin deficient (mld) mutant mice.","date":"1987","source":"Brain research","url":"https://pubmed.ncbi.nlm.nih.gov/2443219","citation_count":20,"is_preprint":false},{"pmid":"32818370","id":"PMC_32818370","title":"Electrochemically Active In Situ Crystalline Lithium-Organic Thin Films by ALD/MLD.","date":"2020","source":"ACS applied materials & interfaces","url":"https://pubmed.ncbi.nlm.nih.gov/32818370","citation_count":20,"is_preprint":false},{"pmid":"6191832","id":"PMC_6191832","title":"Immunocytochemical investigations of murine leukodystrophies. A study of the mutants 'jimpy' (jp) and 'myelin deficient' (mld).","date":"1983","source":"Brain research","url":"https://pubmed.ncbi.nlm.nih.gov/6191832","citation_count":20,"is_preprint":false},{"pmid":"2431744","id":"PMC_2431744","title":"Mice heterozygous for the mld mutation have intermediate levels of myelin basic protein mRNA and its translation products.","date":"1986","source":"Brain research","url":"https://pubmed.ncbi.nlm.nih.gov/2431744","citation_count":20,"is_preprint":false},{"pmid":"6196085","id":"PMC_6196085","title":"In vitro myelin basic protein synthesis in the PNS and CNS of myelin deficient (mld) mutant mice.","date":"1983","source":"Brain research","url":"https://pubmed.ncbi.nlm.nih.gov/6196085","citation_count":19,"is_preprint":false},{"pmid":"12234847","id":"PMC_12234847","title":"Biochemical-genetic analysis and distribution of DES-1, an Ambler class A extended-spectrum beta-lactamase from Desulfovibrio desulfuricans.","date":"2002","source":"Antimicrobial agents and chemotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/12234847","citation_count":19,"is_preprint":false},{"pmid":"16079306","id":"PMC_16079306","title":"Overexpression of des(1-3) insulin-like growth factor 1 in the mammary glands of transgenic mice delays the loss of milk production with prolonged lactation.","date":"2005","source":"Biology of reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/16079306","citation_count":19,"is_preprint":false},{"pmid":"9915875","id":"PMC_9915875","title":"Transgenic hypersecretion of des(1-3) human insulin-like growth factor I in mouse milk has limited effects on the gastrointestinal tract in suckling pups.","date":"1999","source":"The Journal of nutrition","url":"https://pubmed.ncbi.nlm.nih.gov/9915875","citation_count":19,"is_preprint":false},{"pmid":"36639712","id":"PMC_36639712","title":"Nutrient scoring for the DEGS1-FFQ - from food intake to nutrient intake.","date":"2023","source":"BMC nutrition","url":"https://pubmed.ncbi.nlm.nih.gov/36639712","citation_count":18,"is_preprint":false},{"pmid":"19296915","id":"PMC_19296915","title":"VGD and MLD-motifs containing heterodimeric disintegrin viplebedin-2 from Vipera lebetina snake venom. Purification and cDNA cloning.","date":"2009","source":"Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/19296915","citation_count":17,"is_preprint":false},{"pmid":"9205087","id":"PMC_9205087","title":"Biodistribution of 125I-labeled des(1-3) insulin-like growth factor I in tumor-bearing nude mice and its in vitro catabolism.","date":"1997","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/9205087","citation_count":17,"is_preprint":false},{"pmid":"9819060","id":"PMC_9819060","title":"The Des-1 protein, required for central spindle assembly and cytokinesis, is associated with mitochondria along the meiotic spindle apparatus and with the contractile ring during male meiosis in Drosophila melanogaster.","date":"1998","source":"Molecular & general genetics : MGG","url":"https://pubmed.ncbi.nlm.nih.gov/9819060","citation_count":17,"is_preprint":false},{"pmid":"12573816","id":"PMC_12573816","title":"Des (1-3) IGF-I-stimulated growth of human stromal BPH cells is inhibited by a vitamin D3 analogue.","date":"2002","source":"Molecular and cellular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/12573816","citation_count":17,"is_preprint":false},{"pmid":"19754943","id":"PMC_19754943","title":"DNA vaccine containing the mycobacterial hsp65 gene prevented insulitis in MLD-STZ diabetes.","date":"2009","source":"Journal of immune based therapies and vaccines","url":"https://pubmed.ncbi.nlm.nih.gov/19754943","citation_count":16,"is_preprint":false},{"pmid":"10403914","id":"PMC_10403914","title":"Leflunomide protects mice from multiple low dose streptozotocin (MLD-SZ)-induced insulitis and diabetes.","date":"1999","source":"Clinical and experimental immunology","url":"https://pubmed.ncbi.nlm.nih.gov/10403914","citation_count":16,"is_preprint":false},{"pmid":"12745670","id":"PMC_12745670","title":"Des(1-3)IGF-1 treatment normalizes type 1 IGF receptor and phospho-Akt (Thr 308) immunoreactivity in predegenerative retina of diabetic rats.","date":"2003","source":"International journal of experimental diabesity research","url":"https://pubmed.ncbi.nlm.nih.gov/12745670","citation_count":16,"is_preprint":false},{"pmid":"3771560","id":"PMC_3771560","title":"The stimulation by monovalent cations of the amidase activity of bovine des-1-41 light chain activated protein C.","date":"1986","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/3771560","citation_count":15,"is_preprint":false},{"pmid":"37701322","id":"PMC_37701322","title":"A retrospective cohort study of Libmeldy (atidarsagene autotemcel) for MLD: What we have accomplished and what opportunities lie ahead.","date":"2023","source":"JIMD reports","url":"https://pubmed.ncbi.nlm.nih.gov/37701322","citation_count":14,"is_preprint":false},{"pmid":"34332565","id":"PMC_34332565","title":"Emodin inhibits viability, proliferation and promotes apoptosis of hypoxic human pulmonary artery smooth muscle cells via targeting miR-244-5p/DEGS1 axis.","date":"2021","source":"BMC pulmonary medicine","url":"https://pubmed.ncbi.nlm.nih.gov/34332565","citation_count":14,"is_preprint":false},{"pmid":"2997170","id":"PMC_2997170","title":"Des-1-25-fructose-1,6-bisphosphatase, a nonallosteric derivative produced by trypsin treatment of the native protein.","date":"1985","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/2997170","citation_count":14,"is_preprint":false},{"pmid":"32181687","id":"PMC_32181687","title":"DES1: A Key Driver of Lipotoxicity in Metabolic Disease.","date":"2020","source":"DNA and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/32181687","citation_count":14,"is_preprint":false},{"pmid":"12809638","id":"PMC_12809638","title":"Spectrum of mutations in the arylsulfatase A gene in a Canadian DNA collection including two novel frameshift mutations, a new missense mutation (C488R) and an MLD mutation (R84Q) in cis with a pseudodeficiency allele.","date":"2003","source":"Molecular genetics and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/12809638","citation_count":14,"is_preprint":false},{"pmid":"7680515","id":"PMC_7680515","title":"Insulin-like growth factor binding protein-1 from Hep G2 cells is potently inhibited by the truncated IGF-I analogue des-(1-3) IGF-I.","date":"1993","source":"Acta endocrinologica","url":"https://pubmed.ncbi.nlm.nih.gov/7680515","citation_count":14,"is_preprint":false},{"pmid":"2467724","id":"PMC_2467724","title":"The duplicated myelin basic protein gene in mld mutant mice does not impair transcription.","date":"1989","source":"Brain research","url":"https://pubmed.ncbi.nlm.nih.gov/2467724","citation_count":13,"is_preprint":false},{"pmid":"11061266","id":"PMC_11061266","title":"Adult-onset MLD: a gene mutation with isolated polyneuropathy.","date":"2000","source":"Neurology","url":"https://pubmed.ncbi.nlm.nih.gov/11061266","citation_count":13,"is_preprint":false},{"pmid":"16346108","id":"PMC_16346108","title":"Initial Stages in the Biodegradation of the Surfactant Sodium Dodecyltriethoxy Sulfate by Pseudomonas sp. Strain DES1.","date":"1982","source":"Applied and environmental microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/16346108","citation_count":13,"is_preprint":false},{"pmid":"8558556","id":"PMC_8558556","title":"Metachromatic leucodystrophy (MLD) in a patient with a constitutional ring chromosome 22.","date":"1995","source":"Journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/8558556","citation_count":13,"is_preprint":false},{"pmid":"6312432","id":"PMC_6312432","title":"des-(1-13) human beta-endorphin interacts with calmodulin.","date":"1983","source":"Peptides","url":"https://pubmed.ncbi.nlm.nih.gov/6312432","citation_count":13,"is_preprint":false},{"pmid":"2787675","id":"PMC_2787675","title":"A comparison between activated protein C and des-1-41-light chain-activated protein C in reactions with type 1 plasminogen activator inhibitor.","date":"1989","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/2787675","citation_count":13,"is_preprint":false},{"pmid":"17485124","id":"PMC_17485124","title":"A multiplex PCR method discriminating between the TYLCV and TYLCV-Mld clades of tomato yellow leaf curl virus.","date":"2007","source":"Journal of virological methods","url":"https://pubmed.ncbi.nlm.nih.gov/17485124","citation_count":12,"is_preprint":false},{"pmid":"3597424","id":"PMC_3597424","title":"The effect of divalent cations on the amidolytic activity of bovine plasma activated protein C and des-1-41-light chain activated protein C.","date":"1987","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/3597424","citation_count":12,"is_preprint":false},{"pmid":"37195341","id":"PMC_37195341","title":"DEGS1 -related leukodystrophy: a clinical report and review of literature.","date":"2023","source":"Clinical dysmorphology","url":"https://pubmed.ncbi.nlm.nih.gov/37195341","citation_count":11,"is_preprint":false},{"pmid":"37890668","id":"PMC_37890668","title":"The atypical sphingolipid SPB 18:1(14Z);O2 is a biomarker for DEGS1 related hypomyelinating leukodystrophy.","date":"2023","source":"Journal of lipid research","url":"https://pubmed.ncbi.nlm.nih.gov/37890668","citation_count":11,"is_preprint":false},{"pmid":"11156186","id":"PMC_11156186","title":"Brazilin augments cellular immunity in multiple low dose streptozotocin (MLD-STZ) induced type I diabetic mice.","date":"2000","source":"Archives of pharmacal research","url":"https://pubmed.ncbi.nlm.nih.gov/11156186","citation_count":11,"is_preprint":false},{"pmid":"28799099","id":"PMC_28799099","title":"Metachromatic Leukodystrophy (MLD): a Pakistani Family with Novel ARSA Gene Mutation.","date":"2017","source":"Journal of molecular neuroscience : MN","url":"https://pubmed.ncbi.nlm.nih.gov/28799099","citation_count":10,"is_preprint":false},{"pmid":"1703219","id":"PMC_1703219","title":"The endogenous lectin cerebellar soluble lectin and its ligands in central nervous system myelin of myelin-deficient (mld) mutant mice.","date":"1991","source":"Journal of neurochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/1703219","citation_count":10,"is_preprint":false},{"pmid":"2465759","id":"PMC_2465759","title":"The role of myelination in learning performance observed in two strains of myelin-deficient mutant mice (shiverer and mld).","date":"1988","source":"Behavioral and neural biology","url":"https://pubmed.ncbi.nlm.nih.gov/2465759","citation_count":10,"is_preprint":false},{"pmid":"15026521","id":"PMC_15026521","title":"Late onset MLD with normal nerve conduction associated with two novel missense mutations in the ASA gene.","date":"2004","source":"Journal of neurology, neurosurgery, and psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/15026521","citation_count":10,"is_preprint":false},{"pmid":"1883485","id":"PMC_1883485","title":"Expression, purification and characterization of secreted recombinant human insulin-like growth factor-I (IGF-I) and the potent variant des(1-3) IGF-I in Chinese hamster ovary cells.","date":"1991","source":"Journal of molecular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/1883485","citation_count":10,"is_preprint":false},{"pmid":"22139871","id":"PMC_22139871","title":"Myristic acid increases dihydroceramide Δ4-desaturase 1 (DES1) activity in cultured rat hepatocytes.","date":"2011","source":"Lipids","url":"https://pubmed.ncbi.nlm.nih.gov/22139871","citation_count":9,"is_preprint":false},{"pmid":"20487852","id":"PMC_20487852","title":"Density distribution of 2?,3?-cyclic nucleotide 3?-phosphodiesterase and myelin proteins in particulate material from myelin deficient (mld) mutant and control brains.","date":"1982","source":"Neurochemistry international","url":"https://pubmed.ncbi.nlm.nih.gov/20487852","citation_count":9,"is_preprint":false},{"pmid":"22424756","id":"PMC_22424756","title":"Profile of fatty acids, muscle structure and shear force of musculus longissimus dorsi (MLD) in growing pigs as affected by energy and protein or protein restriction followed by realimentation.","date":"2012","source":"Meat science","url":"https://pubmed.ncbi.nlm.nih.gov/22424756","citation_count":9,"is_preprint":false},{"pmid":"3579297","id":"PMC_3579297","title":"The binding of Mn2+ to bovine plasma protein C, des(1-41)-light chain protein C, and activated des(1-41)-light chain activated protein C.","date":"1987","source":"Archives of biochemistry and biophysics","url":"https://pubmed.ncbi.nlm.nih.gov/3579297","citation_count":9,"is_preprint":false},{"pmid":"6120139","id":"PMC_6120139","title":"Heterozygote detection in MLD. allelic mutations at the ARA locus.","date":"1981","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/6120139","citation_count":8,"is_preprint":false},{"pmid":"1465072","id":"PMC_1465072","title":"Insulin-like growth factor I and its variant, des(1-3)IGF-I, improve nitrogen balance and food utilization in rats with renal failure.","date":"1992","source":"Mineral and electrolyte metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/1465072","citation_count":8,"is_preprint":false},{"pmid":"30988556","id":"PMC_30988556","title":"Heterogeneity of Mesenchymal Stromal Cells in Myelodysplastic Syndrome-with Multilineage Dysplasia (MDS-MLD).","date":"2019","source":"Indian journal of hematology & blood transfusion : an official journal of Indian Society of Hematology and Blood Transfusion","url":"https://pubmed.ncbi.nlm.nih.gov/30988556","citation_count":7,"is_preprint":false},{"pmid":"31694723","id":"PMC_31694723","title":"Three novel variants in the arylsulfatase A (ARSA) gene in patients with metachromatic leukodystrophy (MLD).","date":"2019","source":"BMC research notes","url":"https://pubmed.ncbi.nlm.nih.gov/31694723","citation_count":6,"is_preprint":false},{"pmid":"9389551","id":"PMC_9389551","title":"The growth hormone dependent serine protease inhibitor, Spi 2.1 inhibits the des (1-3) insulin-like growth factor-I generating protease.","date":"1997","source":"Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/9389551","citation_count":6,"is_preprint":false},{"pmid":"3793723","id":"PMC_3793723","title":"The effect of monovalent cations on the pre-steady state reaction kinetics of bovine activated plasma protein C and des-1-41-light chain activated plasma protein C.","date":"1987","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/3793723","citation_count":6,"is_preprint":false},{"pmid":"36165222","id":"PMC_36165222","title":"Dihydroceramide desaturase 1 (DES1) promotes anchorage-independent survival downstream of HER2-driven glucose uptake and metabolism.","date":"2022","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/36165222","citation_count":5,"is_preprint":false},{"pmid":"1371758","id":"PMC_1371758","title":"Molecular genetic analysis of the mldr mouse: a spontaneous revertant at the mld locus containing a recombinant myelin basic protein gene.","date":"1992","source":"Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/1371758","citation_count":5,"is_preprint":false},{"pmid":"3584107","id":"PMC_3584107","title":"205Tl+ as a spectroscopic probe of the monovalent cation binding sites of bovine plasma activated protein C and des-1-41-light-chain-activated protein C.","date":"1987","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/3584107","citation_count":5,"is_preprint":false},{"pmid":"30083785","id":"PMC_30083785","title":"Clinical, Molecular, and Computational Analysis Showed a Novel Homozygous Mutation Among the Substrate-Binding Site of ARSA Protein in Consanguineous Family with Late-Infantile MLD.","date":"2018","source":"Journal of molecular neuroscience : MN","url":"https://pubmed.ncbi.nlm.nih.gov/30083785","citation_count":5,"is_preprint":false},{"pmid":"22284439","id":"PMC_22284439","title":"Brain MRI and biological diagnosis in five Tunisians MLD patients.","date":"2012","source":"Diagnostic pathology","url":"https://pubmed.ncbi.nlm.nih.gov/22284439","citation_count":4,"is_preprint":false},{"pmid":"6085770","id":"PMC_6085770","title":"Anticonvulsive treatment of myelin-deficient (mld) mice improves survival and confirms the delayed increase of myelin basic protein.","date":"1984","source":"Neurochemical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/6085770","citation_count":4,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":48338,"output_tokens":3110,"usd":0.095832},"stage2":{"model":"claude-opus-4-6","input_tokens":6487,"output_tokens":2476,"usd":0.141503},"total_usd":0.237335,"stage1_batch_id":"msgbatch_0118RScg3WGaGkaZRtWZbtce","stage2_batch_id":"msgbatch_01Cpfzvtbj42aqp5oYZ5Te2s","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1997,\n      \"finding\": \"DEGS1 (MLD gene product) is a member of the membrane fatty acid desaturase family, contains three consensus histidine-rich motifs (HX3H, HX2HH, HX2HHXFP) characteristic of membrane fatty acid desaturases, is extractable from particulate fractions only with detergent, and localizes to the endoplasmic reticulum. Overexpression inhibits biosynthesis of the EGF receptor without affecting PDGF receptor expression, suggesting a role in biosynthetic processing.\",\n      \"method\": \"Sequence analysis, subcellular fractionation, detergent/salt/urea extraction, immunolocalization to ER, cotransfection overexpression assay\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization experiment and functional consequence of overexpression, single lab\",\n      \"pmids\": [\"9188692\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"DES1 (DEGS1) functions as a retinol isomerase (isomerase-2) in Müller glial cells of the retina; it coimmunoprecipitates with cellular retinaldehyde binding protein (CRALBP), purified DES1 has high isomerase-2 activity in the presence of appropriate cofactors, adenoviral DES1 gene therapy partially rescues biochemical and physiological phenotypes in Rpe65-/- mice, and RNAi knockdown reduces isomerase-2 activity in cultured Müller cells.\",\n      \"method\": \"Co-immunoprecipitation, in vitro isomerase assay with purified protein, RNAi knockdown, adenoviral gene therapy rescue in Rpe65-/- mice\",\n      \"journal\": \"Nature chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — purified protein in vitro activity, co-IP, genetic rescue, and RNAi phenotype, multiple orthogonal methods in one study\",\n      \"pmids\": [\"23143414\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"DEGS1 is the desaturase catalyzing the last step in the main ceramide biosynthetic pathway (dihydroceramide to ceramide). Loss-of-function (pharmacological or genetic ablation) in preadipocytes prevents adipogenesis and decreases lipid accumulation, associated with elevated dihydroceramide content, oxidative stress, cell death, and cell cycle blockage. In vivo pharmacological inhibition of DEGS1 impairs adipocyte differentiation.\",\n      \"method\": \"Pharmacological inhibition, siRNA/genetic knockdown in preadipocytes, lipidomics, in vivo inhibitor treatment\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal loss-of-function approaches (pharmacological + genetic) with specific biochemical and cellular readouts\",\n      \"pmids\": [\"25352638\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"DEGS1 catalyzes the conversion of dihydroceramide (DhCer) to ceramide (Cer) as the final step of de novo ceramide biosynthesis. Mutations in DEGS1 cause marked accumulation of dihydroceramide species and elevated DhCer/Cer ratios in patient fibroblasts and muscle, recapitulated in CRISPR/Cas9 DEGS1-knockout cells and by pharmacological inhibition. Patient fibroblast enzymatic activity was reduced by 80% vs. wild-type. A potentially neurotoxic atypical sphingosine isomer was identified in patient plasma and in cells expressing mutant DEGS1.\",\n      \"method\": \"Whole-exome sequencing, lipidomics in patient fibroblasts and plasma, CRISPR/Cas9 knockout cells, pharmacological inhibition, enzymatic activity assay\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — enzymatic activity measured directly in patient cells and KO cells, lipidomics orthogonally confirm substrate accumulation, replicated by two independent groups simultaneously\",\n      \"pmids\": [\"30620337\", \"30620338\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"DEGS1 encodes C4-dihydroceramide desaturase; missense variants cause accumulation of dihydroceramides, dihydrosphingosine, dihydrosphingosine-1-phosphate, and dihydrosphingomyelins with reduced ceramide, sphingosine, sphingosine-1-phosphate, and monohexosylceramides in patient blood, confirming the enzymatic role in ceramide synthesis pathway.\",\n      \"method\": \"Whole-exome sequencing, Sanger sequencing, lipidomics of whole blood\",\n      \"journal\": \"European journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — lipidomics directly confirm substrate/product imbalance in patients, single lab\",\n      \"pmids\": [\"31186544\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"A rare DEGS1 variant (L175Q) significantly reduces DEGS1 enzymatic activity; CRISPR/Cas9 editing of HepG2 cells confirmed partial loss of function, with heterozygotes showing dramatically reduced indexes of DEGS1 enzymatic activity and large increases in plasma dihydroceramides.\",\n      \"method\": \"CRISPR/Cas9 genome editing, plasma lipidomics, enzymatic activity assay\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — CRISPR-confirmed loss of function combined with enzymatic activity measurement and lipidomics\",\n      \"pmids\": [\"31227640\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Conditional knockout of Des1 in Müller cells of the retina (using Pdgfrα-Cre) causes no gross changes in retinal structure and no effect on cone sensitivity or dark adaptation, but slightly accelerates cone phototransduction termination rate. This indicates Des1 expression in Müller cells is not required for cone visual pigment regeneration in the mouse.\",\n      \"method\": \"Conditional knockout (Cre/lox), electrophysiology (ERG/single-cell recordings), tissue-selective gene recombination, Des1 catalytic activity assay\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — clean conditional KO with functional electrophysiology readout and confirmed enzymatic activity reduction\",\n      \"pmids\": [\"30645148\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Myristic acid increases native DES1 (dihydroceramide Δ4-desaturase 1) enzymatic activity in cultured rat hepatocytes through N-myristoylation of the N-terminal glycine. The wild-type myristoylable form localizes to both ER and mitochondria, whereas a non-myristoylable mutant (N-terminal Gly→Ala) is almost exclusively in the ER, demonstrating that N-myristoylation targets a portion of DES1 from the ER to the mitochondrial outer membrane and increases ceramide levels and apoptosis.\",\n      \"method\": \"Site-directed mutagenesis (Gly→Ala), subcellular fractionation, organelle immunolocalization, enzymatic activity assay in hepatocytes and cell lysates\",\n      \"journal\": \"Lipids\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — mutagenesis of modification site combined with subcellular fractionation and enzymatic activity assay\",\n      \"pmids\": [\"22139871\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"DEGS1 is a mitochondria-associated endoplasmic reticulum membrane (MAM)-resident enzyme. DEGS1 deficiency disrupts core MAM functions: (a) mitochondrial dynamics — hyperfused mitochondrial network with decreased DRP1 activation; (b) cholesterol metabolism — impaired sterol O-acyltransferase activity and decreased cholesteryl esters; (c) phospholipid metabolism — increased phosphatidic acid and phosphatidylserine, decreased phosphatidylethanolamine; (d) lipid droplet biogenesis — increased size and numbers. Increased mitochondrial superoxide production and impaired mitochondrial respiration were also detected.\",\n      \"method\": \"Subcellular fractionation, multiomics (lipidomics, proteomics), enzymatic assays, patient fibroblasts, patient muscle biopsy, mitochondrial morphology imaging, superoxide measurement\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (fractionation, enzymatic assays, multiomics, patient tissue) establishing MAM localization and downstream functional consequences\",\n      \"pmids\": [\"36951944\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"DES1 (DEGS1) catalytic activity is necessary for anchorage-independent survival (AIS) in HER2+ cancer cells; DES1 acts downstream of HER2-driven glucose uptake and metabolism. Overexpression of DES1 is sufficient to drive AIS and in vitro tumorigenicity. DES1 functions as a transducer of HER2-driven glucose metabolic signals.\",\n      \"method\": \"Loss-of-function and gain-of-function (overexpression), anchorage-independent growth assay, epistasis with HER2 pathway\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — genetic loss/gain of function with defined cellular phenotype and pathway placement, single lab\",\n      \"pmids\": [\"36165222\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Two novel DEGS1 missense variants near the C-terminus are characterized; a structural model predicts the substrate-binding site. A regulatory link between DEGS1 and fatty acid desaturase 3 (FADS3) is proposed, as the atypical sphingoid base SPB 18:1(14Z);O2 — formed when DEGS1 is non-functional — is a specific biomarker for pathogenic DEGS1 variants.\",\n      \"method\": \"Structural modeling, plasma lipidomics (dihydrosphingolipids and atypical sphingoid base measurement), variant functional assessment\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — structural model and lipidomics biomarker; functional link is indirect, single lab\",\n      \"pmids\": [\"37890668\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"DEGS1 encodes dihydroceramide desaturase-1 (DES1), a multi-transmembrane endoplasmic reticulum/MAM-resident enzyme that introduces the Δ4-trans double bond into dihydroceramide to generate ceramide as the final step of de novo sphingolipid biosynthesis; its activity is enhanced by N-myristoylation (which also redirects a fraction to the mitochondrial outer membrane), it resides at the MAM where it maintains mitochondrial dynamics, cholesterol/phospholipid homeostasis, and lipid droplet biogenesis, it functions as a retinol isomerase in retinal Müller glia, and loss-of-function mutations cause pathological dihydroceramide accumulation leading to hypomyelinating leukodystrophy.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"DEGS1 encodes dihydroceramide Δ4-desaturase 1 (DES1), the enzyme that catalyzes the final step of de novo sphingolipid biosynthesis by introducing a trans-double bond at the C4 position of dihydroceramide to generate ceramide [PMID:25352638, PMID:30620337]. The enzyme is an integral membrane protein of the endoplasmic reticulum and mitochondria-associated ER membranes (MAMs), containing conserved histidine-rich motifs characteristic of fatty acid desaturases; N-myristoylation of its N-terminal glycine enhances catalytic activity and redirects a fraction to the mitochondrial outer membrane [PMID:9188692, PMID:22139871, PMID:36951944]. DEGS1 deficiency disrupts MAM-dependent processes including mitochondrial dynamics (via impaired DRP1 activation), cholesterol esterification, phospholipid remodeling, and lipid droplet biogenesis, and also functions as a retinol isomerase in retinal Müller glial cells [PMID:36951944, PMID:23143414]. Loss-of-function mutations in DEGS1 cause pathological accumulation of dihydroceramides and generation of a neurotoxic atypical sphingoid base, resulting in hypomyelinating leukodystrophy [PMID:30620337, PMID:30620338].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Establishing that DEGS1 is an ER-resident integral membrane protein of the fatty acid desaturase family provided the first molecular identity and predicted catalytic mechanism for the gene product.\",\n      \"evidence\": \"Sequence analysis, detergent extraction, and immunolocalization in transfected cells\",\n      \"pmids\": [\"9188692\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Enzymatic substrate and product not yet identified\", \"Functional role of histidine motifs not mutagenetically confirmed\", \"No lipid desaturase activity directly measured\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Demonstrating that N-myristoylation of the N-terminal glycine enhances DES1 enzymatic activity and redirects the protein from the ER to the mitochondrial outer membrane revealed a post-translational regulatory mechanism controlling both enzyme activity and subcellular distribution.\",\n      \"evidence\": \"Site-directed mutagenesis (G→A), subcellular fractionation, and enzymatic activity assay in rat hepatocytes\",\n      \"pmids\": [\"22139871\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance of mitochondrial DES1 pool unknown\", \"Whether myristoylation is regulated physiologically not addressed\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identifying DES1 as a retinol isomerase (isomerase-2) in Müller glia, with purified protein activity, co-IP with CRALBP, and partial rescue in Rpe65-/- mice, revealed an unexpected non-sphingolipid function for DEGS1.\",\n      \"evidence\": \"In vitro isomerase assay with purified DES1, co-immunoprecipitation, RNAi knockdown, adenoviral gene therapy in Rpe65-/- mice\",\n      \"pmids\": [\"23143414\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Conditional KO later showed Müller cell DES1 is dispensable for cone pigment regeneration in mouse (see 2019)\", \"Whether isomerase activity is biologically relevant in human retina remains unresolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrating that DEGS1 loss of function blocks adipogenesis with dihydroceramide accumulation, oxidative stress, and cell death established the enzyme as essential for the de novo ceramide biosynthesis pathway and linked its activity to cellular differentiation and survival.\",\n      \"evidence\": \"Pharmacological inhibition and siRNA knockdown in preadipocytes with lipidomics and in vivo inhibitor treatment\",\n      \"pmids\": [\"25352638\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of ceramide deficit vs. dihydroceramide accumulation not resolved\", \"Mechanism linking sphingolipid imbalance to oxidative stress unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identification of pathogenic DEGS1 mutations in patients with hypomyelinating leukodystrophy, confirmed by 80% reduction in enzymatic activity, dihydroceramide accumulation in patient cells, and recapitulation in CRISPR knockout cells, established DEGS1 as a Mendelian disease gene and demonstrated that a neurotoxic atypical sphingoid base is produced when the enzyme is defective.\",\n      \"evidence\": \"Whole-exome sequencing, patient fibroblast enzymatic assays, CRISPR/Cas9 KO cells, plasma and tissue lipidomics across two independent groups\",\n      \"pmids\": [\"30620337\", \"30620338\", \"31186544\", \"31227640\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which atypical sphingoid base causes neurotoxicity not elucidated\", \"Genotype-phenotype correlation across variant spectrum incomplete\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Conditional knockout of Des1 in Müller cells showed no requirement for cone visual pigment regeneration, refining the earlier isomerase-2 finding and indicating functional redundancy or an alternative isomerase pathway in vivo.\",\n      \"evidence\": \"Conditional Cre/lox knockout in mouse Müller cells with ERG and single-cell electrophysiology\",\n      \"pmids\": [\"30645148\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether DES1 isomerase activity is relevant under pathological or aging conditions not tested\", \"Compensation by other isomerases not investigated\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showing that DES1 catalytic activity is necessary and sufficient for anchorage-independent survival downstream of HER2-driven glucose metabolism placed the enzyme in an oncogenic signaling axis.\",\n      \"evidence\": \"Loss- and gain-of-function in HER2+ cancer cells, anchorage-independent growth assay, epistasis analysis\",\n      \"pmids\": [\"36165222\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo tumorigenesis not tested\", \"Mechanism connecting ceramide production to anchorage-independent survival unresolved\", \"Single cancer cell type studied\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Establishing DEGS1 as a MAM-resident enzyme whose deficiency disrupts mitochondrial dynamics, cholesterol/phospholipid metabolism, and lipid droplet biogenesis broadened the pathomechanism beyond sphingolipid imbalance to encompass global organelle-contact-site dysfunction.\",\n      \"evidence\": \"Subcellular fractionation, multi-omics, enzymatic assays, and mitochondrial imaging in patient fibroblasts and muscle biopsies\",\n      \"pmids\": [\"36951944\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether MAM dysfunction is a direct consequence of ceramide depletion or dihydroceramide accumulation not separated\", \"Structural basis for DES1 enrichment at MAMs unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Structural modeling predicted the substrate-binding site and identified an atypical sphingoid base (SPB 18:1(14Z);O2) as a specific biomarker for pathogenic DEGS1 variants, suggesting a regulatory link with FADS3.\",\n      \"evidence\": \"Computational structural modeling and plasma lipidomics in patients with novel C-terminal variants\",\n      \"pmids\": [\"37890668\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No experimental structure available\", \"FADS3 regulatory link not experimentally validated\", \"Biomarker specificity not tested in large cohorts\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the atomic structure of DES1, the mechanism by which dihydroceramide accumulation versus ceramide depletion each contribute to neuropathology, whether the neurotoxic atypical sphingoid base is a primary disease driver, and the physiological relevance of DES1 retinol isomerase activity in humans.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No crystal or cryo-EM structure\", \"Neurotoxicity mechanism of atypical sphingoid base unknown\", \"Relative pathogenic contribution of substrate accumulation vs. product deficit not separated\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [0, 2, 3, 5, 7, 8]},\n      {\"term_id\": \"GO:0016853\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 7, 8]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [7, 8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [2, 3, 4, 5, 7, 8]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [3, 4, 8]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"CRALBP\",\n      \"DRP1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}