id: P48449
gene_symbol: LSS
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  LSS encodes lanosterol synthase (2,3-oxidosqualene-lanosterol cyclase, OSC;
  EC 5.4.99.7), the enzyme that catalyses the polycyclization of (S)-2,3-epoxysqualene
  (2,3-oxidosqualene) to lanosterol. This remarkable single reaction forms the sterol
  nucleus with seven chiral centres, producing the first cyclic sterol and the committed
  precursor of all downstream sterols, including cholesterol. LSS acts immediately after
  squalene epoxidase (SQLE) and constitutes the final committed step of lanosterol
  biosynthesis from farnesyl diphosphate. It is a monotopic (peripheral) protein of the
  endoplasmic reticulum membrane and functions as a monomer, adopting the double
  alpha/alpha toroid fold characteristic of the terpene cyclase/mutase family. In humans,
  biallelic loss-of-function or mislocalizing mutations cause a spectrum of autosomal
  recessive disorders including congenital cataract (CTRCT44), hypotrichosis simplex
  (HYPT14), and alopecia with intellectual disability (APMR4); its product lanosterol
  can reverse crystallin protein aggregation in the lens.
alternative_products:
- name: '1'
  id: P48449-1
- name: '2'
  id: P48449-2
  sequence_note: VSP_045407
- name: '3'
  id: P48449-3
  sequence_note: VSP_046188
existing_annotations:
- term:
    id: GO:0000250
    label: lanosterol synthase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      Phylogenetic (IBA) assertion of the core catalytic activity of LSS, the
      cyclization of (S)-2,3-oxidosqualene to lanosterol. This is the defining molecular
      function of the gene, extensively supported by direct experiment in human and by
      cross-species conservation.
    action: ACCEPT
    reason: >-
      Correct and specific. The IBA call agrees with human experimental evidence
      (EXP PMID:14766201, IMP PMID:26200341, IGI PMID:7639730) and with the UniProt
      catalytic activity annotation (RHEA:14621, EC 5.4.99.7).
    supported_by:
    - reference_id: PMID:7639730
      supporting_text: >-
        Lanosterol synthase [(S)-2,3-epoxysqualene mutase (cyclizing, lanosterol
        forming), EC 5.4.99.7] catalyzes the cyclization of (S)-2,3-oxidosqualene to
        lanosterol in the reaction that forms the sterol nucleus.
- term:
    id: GO:0006695
    label: cholesterol biosynthetic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Phylogenetic (IBA) assignment of LSS to cholesterol biosynthesis. LSS produces
      lanosterol, the first cyclic sterol and the committed precursor of cholesterol,
      so involvement in cholesterol biosynthesis is a core biological-process role.
    action: ACCEPT
    reason: >-
      Well supported. Human experimental evidence links LSS to cholesterol biosynthesis
      (IMP PMID:17186944), and UniProt describes it as the "Key enzyme in the cholesterol
      biosynthesis pathway".
    supported_by:
    - reference_id: file:human/LSS/LSS-uniprot.txt
      supporting_text: Key enzyme in the cholesterol biosynthesis pathway
- term:
    id: GO:0005811
    label: lipid droplet
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      Phylogenetic (IBA) assignment of LSS activity to lipid droplets, supported by
      proteomic co-fractionation of LSS with the lipid-droplet fraction across species.
    action: KEEP_AS_NON_CORE
    reason: >-
      Lipid droplets are contiguous with the endoplasmic reticulum, and many ER lipid
      enzymes co-purify with the LD fraction (PMID:14741744, PMID:21498505). LSS may
      transiently associate with LDs, but its principal, experimentally established
      site of action is the ER membrane. Retain as a non-core localization rather than
      the primary functional compartment.
    supported_by:
    - reference_id: PMID:14741744
      supporting_text: >-
        a fraction enriched with lipid droplets was isolated from a human hepatocyte
        cell line HuH7 using sucrose density gradient centrifugation
- term:
    id: GO:0000250
    label: lanosterol synthase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Automated (IEA) assignment of lanosterol synthase activity from ARBA / RHEA:14621 /
      EC 5.4.99.7. Redundant with the experimentally supported core molecular function.
    action: ACCEPT
    reason: >-
      The electronic mapping (EC 5.4.99.7 to GO:0000250) is exactly correct and matches
      the UniProt catalytic activity annotation and direct experimental evidence.
    supported_by:
    - reference_id: PMID:14766201
      supporting_text: >-
        The monotopic integral membrane protein 2,3-oxidosqualene cyclase (OSC)
        catalyzes the formation of lanosterol the first sterol precursor of cholesterol
        in mammals.
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      Automated (IEA) ER-membrane localization derived from UniProt subcellular-location
      mapping. Matches the experimentally established location of LSS.
    action: ACCEPT
    reason: >-
      Correct and directly corroborated by experiment (EXP PMID:14766201, EXP
      PMID:15525992, IDA PMID:30401459). UniProt records "Endoplasmic reticulum membrane".
    supported_by:
    - reference_id: file:human/LSS/LSS-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Endoplasmic reticulum membrane"
- term:
    id: GO:0005811
    label: lipid droplet
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: located_in
  review:
    summary: >-
      Automated (IEA, InterPro IPR018333 squalene cyclase) lipid-droplet localization.
      Duplicates the IBA and IDA lipid-droplet calls.
    action: KEEP_AS_NON_CORE
    reason: >-
      Consistent with proteomic lipid-droplet detection of LSS, but the lipid droplet
      is a secondary compartment; the core, experimentally established location is the
      ER membrane. Keep as non-core.
    supported_by:
    - reference_id: PMID:21498505
      supporting_text: >-
        both enzymes additionally localize to lipid droplets (LDs), which consist of a
        core of neutral lipids surrounded by a monolayer of phospholipid
- term:
    id: GO:0006695
    label: cholesterol biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: >-
      Automated (ARBA) assignment to cholesterol biosynthetic process. Duplicates the
      IBA and TAS cholesterol-biosynthesis calls.
    action: ACCEPT
    reason: >-
      Correct. LSS produces lanosterol, the committed precursor of cholesterol; this is
      a core biological-process role supported by human experiment (IMP PMID:17186944).
    supported_by:
    - reference_id: file:human/LSS/LSS-uniprot.txt
      supporting_text: Key enzyme in the cholesterol biosynthesis pathway
- term:
    id: GO:0016104
    label: triterpenoid biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: >-
      Automated (IEA, InterPro IPR018333) assignment to triterpenoid biosynthetic
      process, reflecting the broad squalene/oxidosqualene cyclase family mapping.
    action: KEEP_AS_NON_CORE
    reason: >-
      Not wrong at the family level: lanosterol is a triterpenoid and oxidosqualene
      cyclases generically make triterpenoids. In humans, however, the biologically
      meaningful process is the specific cholesterol/sterol biosynthetic pathway
      (GO:0006695), of which this term is a broader relative. Retain as non-core rather
      than as the primary process.
    supported_by:
    - reference_id: PMID:15525992
      supporting_text: >-
        In a highly selective cyclization reaction OSC forms lanosterol with seven
        chiral centres starting from the linear substrate 2,3-oxidosqualene.
- term:
    id: GO:0016866
    label: intramolecular transferase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      Automated (IEA, InterPro) assignment of the parent activity "intramolecular
      transferase activity". Lanosterol synthase activity (GO:0000250) is a descendant
      of this term.
    action: MODIFY
    reason: >-
      Correct branch but far too general. The precise, experimentally established
      molecular function is lanosterol synthase activity (GO:0000250), a specific child
      of the intramolecular oxidosqualene/lanosterol cyclase lineage. Replace with the
      specific term.
    proposed_replacement_terms:
    - id: GO:0000250
      label: lanosterol synthase activity
    supported_by:
    - reference_id: PMID:7639730
      supporting_text: >-
        Lanosterol synthase [(S)-2,3-epoxysqualene mutase (cyclizing, lanosterol
        forming), EC 5.4.99.7] catalyzes the cyclization of (S)-2,3-oxidosqualene to
        lanosterol in the reaction that forms the sterol nucleus.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: >-
      Seven binary protein-protein interactions (YIF1A, AQP6, CIB1, SLC10A1, SLC10A6,
      TMEM167B, TMEM86B) from a high-throughput yeast two-hybrid interactome map (HuRI),
      annotated as the uninformative parent term protein binding.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      "protein binding" (GO:0005515) conveys no specific molecular function and the
      interactions derive from a proteome-wide binary screen with no functional
      interpretation for LSS. The partners (several ER/membrane transporters and a
      trafficking factor) are consistent with LSS residing in the ER membrane but do
      not define a distinct function. Per curation policy the experimental IPI is
      retained but flagged as an over-annotation rather than removed.
    supported_by:
    - reference_id: file:human/LSS/LSS-uniprot.txt
      supporting_text: "P48449; Q99828: CIB1; NbExp=3; IntAct=EBI-3930711, EBI-372594;"
- term:
    id: GO:0006695
    label: cholesterol biosynthetic process
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9969896
  qualifier: involved_in
  review:
    summary: >-
      Reactome traceable assertion placing LSS in cholesterol biosynthesis (the
      lanosterol biosynthesis module of the cholesterol pathway).
    action: ACCEPT
    reason: >-
      Correct and authoritative. Reactome documents that cholesterol biosynthesis
      proceeds through lanosterol, the product of LSS; this is a core process role.
    supported_by:
    - reference_id: Reactome:R-HSA-9969896
      supporting_text: >-
        Cholesterol biosynthesis begins with the transformation of cytosolic acetyl CoA
        into lanosterol in a sequence of 15 reactions
- term:
    id: GO:0000250
    label: lanosterol synthase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-191366
  qualifier: enables
  review:
    summary: >-
      Reactome traceable assertion of the core catalytic function: LSS cyclizes squalene
      2,3-epoxide to lanosterol.
    action: ACCEPT
    reason: >-
      Correct and specific; matches the defining catalytic activity of LSS and all
      experimental evidence.
    supported_by:
    - reference_id: Reactome:R-HSA-191366
      supporting_text: >-
        Lanosterol synthase (LSS) catalyzes the cyclization of squalene 2,3-epoxide to
        lanosterol, a reaction that forms the sterol nucleus
- term:
    id: GO:0000250
    label: lanosterol synthase activity
  evidence_type: EXP
  original_reference_id: PMID:14766201
  qualifier: enables
  review:
    summary: >-
      Direct experimental demonstration of lanosterol synthase (oxidosqualene cyclase)
      activity using recombinant human OSC purified from Pichia pastoris, active as a
      monomer, with IC50 for the reference inhibitor matching human liver microsomal OSC.
    action: ACCEPT
    reason: >-
      Gold-standard experimental support for the core molecular function.
    supported_by:
    - reference_id: PMID:14766201
      supporting_text: >-
        The monotopic integral membrane protein 2,3-oxidosqualene cyclase (OSC)
        catalyzes the formation of lanosterol the first sterol precursor of cholesterol
        in mammals.
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: EXP
  original_reference_id: PMID:14766201
  qualifier: located_in
  review:
    summary: >-
      Experimental characterization of human OSC as a monotopic integral/peripheral
      membrane protein of the ER, active as a monomer.
    action: ACCEPT
    reason: >-
      Directly supports ER-membrane localization; consistent with the crystallographic
      and disease-gene studies (PMID:15525992, PMID:30401459) and UniProt.
    supported_by:
    - reference_id: PMID:14766201
      supporting_text: >-
        The monotopic integral membrane protein 2,3-oxidosqualene cyclase (OSC)
        catalyzes the formation of lanosterol
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: EXP
  original_reference_id: PMID:15525992
  qualifier: located_in
  review:
    summary: >-
      Crystal structures (PDB 1W6J, 1W6K) of the human membrane protein OSC, confirming
      it is a membrane-bound enzyme localized to the ER membrane.
    action: ACCEPT
    reason: >-
      Structural study of the membrane-bound human enzyme corroborating ER-membrane
      localization and defining the active site of the cyclization reaction.
    supported_by:
    - reference_id: PMID:15525992
      supporting_text: >-
        the formation of the steroid scaffold is catalysed exclusively by the
        membrane-bound oxidosqualene cyclase (OSC; lanosterol synthase)
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IDA
  original_reference_id: PMID:30401459
  qualifier: located_in
  review:
    summary: >-
      Immunofluorescence localization of wild-type LSS to the endoplasmic reticulum in
      keratinocytes; hypotrichosis-causing mutants are partly mislocalized outside the ER.
    action: ACCEPT
    reason: >-
      Direct assay (IDA) confirming ER localization of LSS and showing that disease
      mutations disrupt correct ER localization.
    supported_by:
    - reference_id: PMID:30401459
      supporting_text: >-
        wild-type LSS was localized in the endoplasmic reticulum (ER), whereas mutant
        LSS proteins were localized in part outside of the ER
- term:
    id: GO:0000250
    label: lanosterol synthase activity
  evidence_type: IMP
  original_reference_id: PMID:26200341
  qualifier: enables
  review:
    summary: >-
      Mutational evidence: two congenital-cataract LSS missense mutations (W581R, G588S)
      impair the catalytic function of LSS, demonstrating that LSS activity depends on
      these conserved residues.
    action: ACCEPT
    reason: >-
      Supports the core molecular function through loss-of-function disease variants
      that abolish lanosterol synthase activity.
    supported_by:
    - reference_id: PMID:26200341
      supporting_text: >-
        Both of these mutations affect highly conserved amino acid residues and impair
        key catalytic functions of LSS.
- term:
    id: GO:0000250
    label: lanosterol synthase activity
  evidence_type: IGI
  original_reference_id: PMID:7639730
  qualifier: enables
  review:
    summary: >-
      Genetic complementation: the human LSS (OSC) gene rescued a yeast lanosterol
      synthase-deficient mutant (SMY8; yeast ERG7, UniProtKB:P38604), and a cell-free
      homogenate of the complemented strain converted 2,3-oxidosqualene to lanosterol.
    action: ACCEPT
    reason: >-
      Functional (interspecies genetic interaction / complementation) evidence directly
      establishing that LSS encodes an active lanosterol synthase.
    supported_by:
    - reference_id: PMID:7639730
      supporting_text: >-
        The yeast lanosterol synthase deficient mutant SMY8 was complemented by the
        human gene, and a cell-free homogenate of SMY8 expressing the human gene was
        shown to convert 2,3-oxidosqualene to lanosterol.
- term:
    id: GO:0006694
    label: steroid biosynthetic process
  evidence_type: IMP
  original_reference_id: PMID:26200341
  qualifier: involved_in
  review:
    summary: >-
      Involvement of LSS in steroid/sterol biosynthesis, inferred from disease mutations
      that impair LSS catalytic function within the cholesterol synthesis pathway.
    action: KEEP_AS_NON_CORE
    reason: >-
      Correct but general: steroid biosynthetic process is a broad parent of the more
      specific cholesterol/sterol biosynthetic process that captures the biologically
      precise role of LSS. Retain as a valid non-core annotation.
    supported_by:
    - reference_id: PMID:26200341
      supporting_text: >-
        It is synthesized by lanosterol synthase (LSS) in a key cyclization reaction of
        a cholesterol synthesis pathway.
- term:
    id: GO:0031647
    label: regulation of protein stability
  evidence_type: IMP
  original_reference_id: PMID:26200341
  qualifier: involved_in
  review:
    summary: >-
      Annotation derived from the finding that LSS, through its product lanosterol,
      prevents intracellular aggregation of cataract-causing mutant crystallins and can
      reverse preformed lens protein aggregates.
    action: KEEP_AS_NON_CORE
    reason: >-
      This is a downstream, indirect consequence of the LSS product lanosterol acting as
      a small-molecule chaperone on lens crystallins, not a direct molecular activity of
      LSS on protein stability. It is a genuine, disease-relevant phenotype but not a
      core function; retain as non-core.
    supported_by:
    - reference_id: PMID:26200341
      supporting_text: >-
        Engineered expression of wild-type, but not mutant, LSS prevents intracellular
        protein aggregation of various cataract-causing mutant crystallins.
- term:
    id: GO:0016020
    label: membrane
  evidence_type: HDA
  original_reference_id: PMID:19946888
  qualifier: located_in
  review:
    summary: >-
      High-throughput mass-spectrometry detection of LSS in the membrane proteome of an
      NK-like cell line.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      The generic parent term "membrane" is subsumed by the specific, experimentally
      supported endoplasmic reticulum membrane localization (GO:0005789). It adds no
      information beyond the more precise calls and is uninformative on its own.
    supported_by:
    - reference_id: PMID:19946888
      supporting_text: >-
        approximately 40% of the identified proteins were predicted as plausible
        membrane proteins
- term:
    id: GO:0005811
    label: lipid droplet
  evidence_type: IDA
  original_reference_id: PMID:21498505
  qualifier: located_in
  review:
    summary: >-
      Lipid-droplet localization detected in a study of LPCAT1/2, in which LSS was
      identified among lipid-droplet-associated proteins.
    action: KEEP_AS_NON_CORE
    reason: >-
      Lipid droplets bud from and remain contiguous with the ER, so monotopic ER
      enzymes such as LSS co-fractionate with LDs. Real but secondary to the core ER
      localization; retain as non-core.
    supported_by:
    - reference_id: PMID:21498505
      supporting_text: >-
        both enzymes additionally localize to lipid droplets (LDs), which consist of a
        core of neutral lipids surrounded by a monolayer of phospholipid
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1655828
  qualifier: located_in
  review:
    summary: >-
      Reactome traceable assertion of ER-membrane localization (from the LSS expression
      event).
    action: ACCEPT
    reason: >-
      Consistent with experimental ER-membrane localization; redundant with the EXP/IDA
      annotations but correct.
    supported_by:
    - reference_id: Reactome:R-HSA-191366
      supporting_text: LSS is located on the ER membrane and is active in monomeric form
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-191366
  qualifier: located_in
  review:
    summary: >-
      Reactome traceable assertion that LSS is located on the ER membrane and active as
      a monomer, in the lanosterol-forming cyclization reaction.
    action: ACCEPT
    reason: >-
      Correct; matches experimental evidence for ER-membrane localization.
    supported_by:
    - reference_id: Reactome:R-HSA-191366
      supporting_text: LSS is located on the ER membrane and is active in monomeric form
- term:
    id: GO:0005811
    label: lipid droplet
  evidence_type: IDA
  original_reference_id: PMID:14741744
  qualifier: located_in
  review:
    summary: >-
      LSS identified by proteomics in the lipid-droplet-enriched fraction isolated from
      the human hepatocyte cell line HuH7.
    action: KEEP_AS_NON_CORE
    reason: >-
      Co-fractionation of an ER lipid enzyme with the lipid-droplet fraction is expected
      given ER-LD continuity. Genuine detection but a secondary compartment; retain as
      non-core relative to the core ER-membrane localization.
    supported_by:
    - reference_id: PMID:14741744
      supporting_text: >-
        a fraction enriched with lipid droplets was isolated from a human hepatocyte
        cell line HuH7 using sucrose density gradient centrifugation
- term:
    id: GO:0006695
    label: cholesterol biosynthetic process
  evidence_type: IMP
  original_reference_id: PMID:17186944
  qualifier: involved_in
  review:
    summary: >-
      Involvement in cholesterol biosynthesis inferred from pharmacological inhibition of
      oxidosqualene:lanosterol cyclase (OSC/LSS), which reduced cholesterol synthesis and
      diverted flux toward the oxysterol LXR agonist 24(S),25-epoxycholesterol.
    action: ACCEPT
    reason: >-
      Directly supports the core biological-process role of LSS in cholesterol
      biosynthesis; blocking LSS lowers cholesterol synthesis.
    supported_by:
    - reference_id: PMID:17186944
      supporting_text: >-
        THP-1 human macrophages incubated with the OSC inhibitor (OSCi) RO0714565 (15
        nM) significantly reduced cholesterol synthesis
core_functions:
- description: >-
    Lanosterol synthase (2,3-oxidosqualene-lanosterol cyclase): catalyses the
    polycyclization of (S)-2,3-epoxysqualene to lanosterol at the endoplasmic reticulum
    membrane, forming the sterol nucleus and the committed precursor of cholesterol.
  molecular_function:
    id: GO:0000250
    label: lanosterol synthase activity
  directly_involved_in:
  - id: GO:0006695
    label: cholesterol biosynthetic process
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  supported_by:
  - reference_id: PMID:14766201
    supporting_text: >-
      The monotopic integral membrane protein 2,3-oxidosqualene cyclase (OSC) catalyzes
      the formation of lanosterol the first sterol precursor of cholesterol in mammals.
  - reference_id: PMID:7639730
    supporting_text: >-
      Lanosterol synthase [(S)-2,3-epoxysqualene mutase (cyclizing, lanosterol forming),
      EC 5.4.99.7] catalyzes the cyclization of (S)-2,3-oxidosqualene to lanosterol in the
      reaction that forms the sterol nucleus.
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: file:human/LSS/LSS-uniprot.txt
  title: UniProtKB entry P48449 (LSS_HUMAN), Lanosterol synthase
  findings: []
- id: PMID:14741744
  title: Identification of major proteins in the lipid droplet-enriched fraction isolated
    from the human hepatocyte cell line HuH7.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Proteomics of the HuH7 lipid-droplet fraction; supports lipid-droplet
      co-fractionation of LSS but not its core ER-membrane localization.
- id: PMID:14766201
  title: The monotopic membrane protein human oxidosqualene cyclase is active as monomer.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Direct characterization of recombinant human OSC: catalytic activity, monomeric
      state, and monotopic ER-membrane nature. Anchors both the MF and ER-location
      annotations.
- id: PMID:15525992
  title: Insight into steroid scaffold formation from the structure of human oxidosqualene
    cyclase.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Crystal structures (PDB 1W6J/1W6K) of the human membrane-bound enzyme; supports
      MF, membrane localization, and active-site mechanism.
- id: PMID:17186944
  title: Selective up-regulation of LXR-regulated genes ABCA1, ABCG1, and APOE in
    macrophages through increased endogenous synthesis of 24(S),25-epoxycholesterol.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Pharmacological OSC inhibition lowers cholesterol synthesis; supports LSS role in
      cholesterol biosynthetic process (IMP).
- id: PMID:19946888
  title: Defining the membrane proteome of NK cells.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      High-throughput membrane proteome; supports only the generic "membrane" call,
      subsumed by the specific ER-membrane annotation.
- id: PMID:21498505
  title: Human lysophosphatidylcholine acyltransferases 1 and 2 are located in lipid
    droplets where they catalyze the formation of phosphatidylcholine.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      LPCAT1/2 study in which LSS was among lipid-droplet-associated proteins; supports
      non-core lipid-droplet localization.
- id: PMID:26200341
  title: Lanosterol reverses protein aggregation in cataracts.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Identifies CTRCT44 LSS mutations (W581R, G588S) impairing catalysis; shows
      lanosterol (LSS product) reverses crystallin aggregation. Basis of the IMP MF,
      steroid-biosynthesis, and protein-stability annotations.
- id: PMID:30401459
  title: Bi-allelic Mutations in LSS, Encoding Lanosterol Synthase, Cause Autosomal-Recessive
    Hypotrichosis Simplex.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      IF localization of wild-type LSS to the ER (IDA) and mislocalization of HYPT14
      mutants; links LSS/cholesterol pathway to hair-follicle biology.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      HuRI Y2H interactome; source of seven bare protein-binding (GO:0005515) IPIs for
      LSS with no functional interpretation.
- id: PMID:7639730
  title: Molecular cloning of the human gene encoding lanosterol synthase from a liver
    cDNA library.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Cloning of human OSC/LSS and yeast-mutant complementation demonstrating lanosterol
      synthase activity; basis of the IGI MF annotation.
- id: Reactome:R-HSA-1655828
  title: Expression of Lanosterol Synthase (LSS)
  findings: []
- id: Reactome:R-HSA-191366
  title: Squalene 2,3-epoxide cyclizes, forming lanosterol
  findings: []
- id: Reactome:R-HSA-9969896
  title: Lanosterol biosynthesis
  findings: []
proposed_new_terms: []
suggested_questions:
- question: >-
    Does LSS have any non-catalytic (moonlighting) role in the ER membrane beyond
    producing lanosterol, or are all its phenotypes attributable to loss of
    lanosterol/downstream sterol synthesis?
- question: >-
    Is the lipid-droplet localization functionally meaningful (a site of active sterol
    synthesis) or purely a consequence of ER-lipid-droplet continuity during
    fractionation?
suggested_experiments:
- description: >-
    Quantitative sterol-flux and lens-crystallin aggregation assays comparing wild-type
    LSS with CTRCT44 (W581R, G588S) and HYPT14 (L102V, L248P, F391S) variants to separate
    catalytic loss from mislocalization effects.
- description: >-
    Subcellular fractionation plus proximity labeling to test whether catalytically
    active LSS is genuinely present on lipid droplets versus co-purifying with
    ER-derived membrane.