LRIT2 is a type-I single-pass membrane glycoprotein with an extracellular leucine-rich-repeat region, an immunoglobulin-like domain, and a fibronectin type-III domain followed by a short cytoplasmic tail. Human cDNA evidence supports two splice isoforms; isoform 2 replaces canonical Asp297 with an eleven-residue sequence, producing a net ten-residue extension within the immunoglobulin-like domain. A human isoform-1 clone was obtained from retina, and expression resources describe retinal enrichment, but the endogenous human protein's cellular localization and physiological role have not been established. Curated orthology evidence suggests association with LRIT1, while zebrafish ortholog knockdown produced reduced eye size. These findings connect LRIT2 to ocular biology without yet defining a conserved molecular activity or a normal human retinal function.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0016020 membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: This electronic annotation maps the reviewed UniProt subcellular-location statement "Membrane; Single-pass type I membrane protein" to the broad GO membrane term. The topology is consistent with LRIT2's predicted N-terminal signal peptide and transmembrane helix at residues 466-486. Reason: Membrane is an appropriately conservative location for this type I single-pass protein. The evidence does not identify a specific cellular membrane, so the annotation should be retained as written rather than narrowed to plasma membrane or another compartment. It is kept outside a core function because it is an inferred broad topology statement and no molecular activity or physiological process has been established for human LRIT2. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB-SubCell:SL-0162 · UniProt subcellular location - Membrane SOURCE WEAK OR INFERRED The controlled-vocabulary source exactly matches the GOA WITH/FROM field and is consistent with UniProt's single-pass type I topology, but no direct human LRIT2 localization experiment is cited. |
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Download this section (compressed HTML)Q: What extracellular ligand or membrane partner binds human LRIT2, and does LRIT2 alter that partner's localization or signaling?
Suggested experts: Retinal membrane-protein experts, Cell-surface interaction experts
Q: Which human retinal cell types express LRIT2 protein, and at which membrane compartment is it enriched?
Suggested experts: Human retinal atlas experts, Ocular cell biologists
Q: Is an endogenous LRIT1-LRIT2 complex present, and is it required for either protein's trafficking or retinal function?
Suggested experts: Photoreceptor synapse experts, Quantitative interaction biologists
Q: Does the isoform-2 replacement/extension within the immunoglobulin-like domain change LRIT2 folding, surface delivery, or partner specificity?
Suggested experts: Protein-folding experts, Isoform biology experts
Experiment: Introduce an endogenous extracellular tag into LRIT2 in human retinal organoids, perform cell-surface proximity labeling and affinity purification, and validate candidate partners by reciprocal co-immunoprecipitation and purified-ectodomain binding assays.
Hypothesis: LRIT2 has an endogenous extracellular binding partner in human retinal cells.
Type: endogenous interaction proteomics
Experiment: Generate isogenic LRIT2-null and rescue retinal organoids, profile cell-type composition and synaptic connectivity, and assay photoreceptor-to-bipolar signaling without assuming the zebrafish small-eye phenotype transfers directly.
Hypothesis: LRIT2 contributes to a discrete developmental or signaling phenotype in the human retina.
Type: human retinal organoid genetics
Experiment: Compare LRIT1, LRIT2, and double knockouts with endogenous interaction imaging and matched rescue in retinal cells, quantifying trafficking, synapse organization, and light-response phenotypes.
Hypothesis: LRIT1 and LRIT2 form a context-dependent retinal complex but have nonredundant physiological outputs.
Type: genetic interaction and cell biology
Experiment: Quantify isoform-specific expression in human retina, then compare purified ectodomain folding, cell-surface abundance, interaction spectra, and rescue of any LRIT2-null phenotype for isoforms 1 and 2.
Hypothesis: The isoform-2 immunoglobulin-domain replacement/extension changes surface delivery or partner recognition.
Type: isoform-resolved structure-function analysis
What is not known — curated, literature-grounded statements of the open unknowns (the inverse of core functions).
Gap: The molecular activity and endogenous interaction partners of human LRIT2 are unknown.
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Significance: A direct molecular activity is needed before LRIT2 can be assigned a core function rather than only membrane topology.
What would resolve it: Identify endogenous LRIT2 partners in human retinal cells by affinity purification and proximity labeling, then validate direct binding and functional consequences with purified ectodomains and loss-of-function rescue.
Gap: The cell types, subcellular sites, and physiological role of endogenous human LRIT2 in the eye have not been established.
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Significance: Retinal cDNA provenance and cross-species eye phenotypes do not identify a human retinal process or distinguish developmental from synaptic roles.
What would resolve it: Map endogenous LRIT2 RNA and protein in human donor retina and retinal organoids, then perturb LRIT2 in matched photoreceptor and bipolar-cell systems and measure development, connectivity, and visual-signaling outputs.
Provenance (the field's own admissions):
Gap: Whether LRIT2 associates with LRIT1 endogenously, and whether that association has a conserved retinal consequence, remains unresolved.
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Significance: The curated association is transferred from mouse and does not establish a stable human heterodimer, an interaction interface, or shared LRIT1 synaptic biology.
What would resolve it: Test endogenous LRIT1-LRIT2 proximity and stoichiometry in retinal cell types, followed by single and double perturbations that distinguish shared, redundant, and opposing phenotypes.
Gap: The expression, localization, and partner specificity of LRIT2 isoforms 1 and 2 have not been compared.
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Significance: Isoform 2 alters the immunoglobulin-like domain, so sequence-level variation may affect ectodomain folding or partner recognition, but no functional specialization has been demonstrated.
What would resolve it: Use long-read retinal transcriptomics, isoform-specific proteomics, cell-surface trafficking assays, and quantitative partner-binding measurements for both endogenous isoforms.
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