Affinage

TMEM263

Transmembrane protein 263 · UniProt Q8WUH6

Round 2 corrected
Length
116 aa
Mass
11.7 kDa
Annotated
2026-04-28
39 papers in source corpus 5 papers cited in narrative 5 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TMEM263 is a two-pass transmembrane ER-resident protein required for postnatal longitudinal growth and skeletal development across vertebrates. Loss-of-function mutations in chickens, mice, zebrafish, and humans cause dwarfism and skeletal dysplasia; in mice, Tmem263 deletion reduces hepatic growth hormone receptor (GHR) expression and impairs GH-induced JAK2/STAT5 signaling, lowering circulating IGF-1 and feminizing the male liver transcriptome (PMID:38241182). TMEM263 localizes to the ER and lipid droplets, where its transmembrane hairpin domain promotes neutral lipid condensation and lipid droplet biogenesis, linking lipid droplet formation to the organismal growth phenotype [PMID:bio_10.1101_2025.07.04.663055]. Homozygous frameshift mutations in TMEM263 cause autosomal recessive lethal skeletal dysplasia in humans (PMID:34238371).

Mechanistic history

Synthesis pass · year-by-year structured walk · 4 steps
  1. 2018 Medium

    Identification of a causal loss-of-function variant in TMEM263 established the gene as a determinant of body size, answering whether TMEM263 is required for normal skeletal growth in a vertebrate model.

    Evidence Whole-genome sequencing and fine mapping of autosomal dwarf chickens identified a nonsense mutation (p.Trp59*) in TMEM263 fully associated with ~30% growth reduction

    PMID:29930570

    Open questions at the time
    • Reported interaction with GH1 lacked experimental detail and independent validation
    • Mechanism linking TMEM263 to growth was not established
    • Relevance to mammalian physiology was not yet tested
  2. 2021 Medium

    Discovery of a human loss-of-function variant extended the growth requirement to humans and established TMEM263 as a candidate disease gene for autosomal recessive skeletal dysplasia.

    Evidence Whole exome sequencing in a human fetus with lethal rhizomelic skeletal dysplasia identified a homozygous frameshift in TMEM263

    PMID:34238371

    Open questions at the time
    • Single family; no functional rescue or additional kindreds reported
    • Molecular mechanism of skeletal defect was not addressed
    • Tissue-specific role of TMEM263 was unknown
  3. 2024 High

    A mouse knockout model revealed the molecular mechanism underlying TMEM263-dependent growth: TMEM263 is required for hepatic GHR expression and GH-induced JAK2/STAT5 signaling, linking its loss to IGF-1 deficiency and dwarfism.

    Evidence Germline Tmem263-KO mice analyzed by serum IGF-1 measurement, hepatic GHR expression, JAK2/STAT5 phosphorylation assays, and liver transcriptomics with comparison to hypophysectomized and Stat5b-null mice

    PMID:38241182

    Open questions at the time
    • How TMEM263 maintains GHR expression at the molecular level was not determined
    • Whether the GH/IGF-1 axis disruption is cell-autonomous in hepatocytes was not resolved
    • No structural information for TMEM263 or its interaction with GHR was provided
  4. 2025 Medium

    Defining TMEM263 as an ER-resident lipid droplet biogenesis factor provided a cell-biological mechanism — neutral lipid condensation in the ER membrane — potentially upstream of the GH signaling defect.

    Evidence ER protein screen, live-cell imaging, transmembrane hairpin mutagenesis, lipid droplet formation assays in cells and zebrafish (preprint)

    PMID:bio_10.1101_2025.07.04.663055

    Open questions at the time
    • Preprint not yet peer-reviewed
    • Causal link between lipid droplet biogenesis defect and impaired GHR/JAK2/STAT5 signaling has not been established
    • Whether TMEM263-dependent lipid droplet formation is relevant in hepatocytes specifically remains untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • The central unresolved question is how TMEM263's role in ER-localized lipid droplet biogenesis mechanistically connects to its requirement for hepatic GHR surface expression and GH/IGF-1 axis integrity.
  • No structural model of the TMEM263 transmembrane hairpin or its lipid-binding interface exists
  • Direct physical interaction partners in the GHR trafficking or maturation pathway are unknown
  • Tissue-specific conditional knockouts have not been reported

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008289 lipid binding 1
Localization
GO:0005783 endoplasmic reticulum 1 GO:0005811 lipid droplet 1
Pathway
R-HSA-1266738 Developmental Biology 3 R-HSA-162582 Signal Transduction 1
Partners
GHR

Evidence

Reading pass · 5 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2018 A nonsense mutation NP_001006244.1:p.(Trp59*) in TMEM263 truncates the protein within its membrane-spanning domain and is completely associated with autosomal dwarfism (adw) in chickens, causing ~30% growth reduction with short shank, establishing a loss-of-function causal variant. The protein was also reported to interact with growth hormone 1 (GH1). Whole-genome sequencing, fine mapping, and genetic association in normal vs. dwarf chickens Frontiers in genetics Medium 29930570
2019 TMEM263 (Tmem263) was detected in a proximity-labeling (BioID) assay as part of the shared interactome of dopamine transporter (DAT) and glutamate transporter (GLT-1) in hippocampal HT22 cells, indicating close spatial proximity to both transporters in the plasma membrane context. Proximity labeling (BioID) in HT22 cells Neuropharmacology Low 30885609
2021 A homozygous frameshift mutation in TMEM263 was identified by whole exome sequencing in a human fetus with severe lethal skeletal dysplasia (severe rhizomelic dysplasia and pathologic shortening of ribs), establishing TMEM263 as a candidate gene for human autosomal recessive skeletal dysplasia and implicating it in the growth hormone signaling pathway. Whole exome sequencing (WES) and bioinformatics analysis in an affected human fetus Human genomics Medium 34238371
2024 Deletion of Tmem263 in mice causes severe postnatal growth failure, proportional dwarfism, and impaired skeletal acquisition. Tmem263-null mice develop low circulating IGF-1 levels and reduced bone mass by P21 due to a disrupted GH/IGF-1 axis. The mechanism involves reduced hepatic GH receptor (GHR) expression and impaired GH-induced JAK2/STAT5 signaling. Loss of GH signaling feminizes the liver transcriptome of male mice, with expression profiles resembling wild-type female, hypophysectomized male, and Stat5b-null male mice. Germline Tmem263 knockout mouse model; serum IGF-1 measurement; hepatic GHR expression analysis; JAK2/STAT5 phosphorylation assay; liver transcriptome profiling eLife High 38241182
2025 TMEM263 is an ER-resident protein with two transmembrane domains that fold into a hairpin structure essential for its localization to the ER and to lipid droplets. TMEM263 is both necessary and sufficient for lipid droplet formation; it interacts with and supports condensation of neutral lipids in a bilayer to promote lipid droplet biogenesis and growth. Loss of TMEM263 in cells and in zebrafish significantly impairs lipid droplet formation, providing a mechanistic link between TMEM263-dependent lipid droplet biology and the organismal growth defects/dwarfism observed upon its loss. ER-resident protein screen; live-cell imaging; domain mutagenesis (transmembrane hairpin); lipid droplet formation assays in cells; zebrafish loss-of-function model bioRxivpreprint Medium bio_10.1101_2025.07.04.663055

Source papers

Stage 0 corpus · 39 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2012 Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture. Nature genetics 958 22504420
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
2005 Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. Genome research 409 16344560
1996 Normalization and subtraction: two approaches to facilitate gene discovery. Genome research 401 8889548
2021 A proximity-dependent biotinylation map of a human cell. Nature 339 34079125
2007 hORFeome v3.1: a resource of human open reading frames representing over 10,000 human genes. Genomics 222 17207965
2018 An AP-MS- and BioID-compatible MAC-tag enables comprehensive mapping of protein interactions and subcellular localizations. Nature communications 201 29568061
2020 Systems analysis of RhoGEF and RhoGAP regulatory proteins reveals spatially organized RAC1 signalling from integrin adhesions. Nature cell biology 194 32203420
2020 A High-Density Human Mitochondrial Proximity Interaction Network. Cell metabolism 148 32877691
2008 Systematic identification of mRNAs recruited to argonaute 2 by specific microRNAs and corresponding changes in transcript abundance. PloS one 148 18461144
2016 Glutamine Triggers Acetylation-Dependent Degradation of Glutamine Synthetase via the Thalidomide Receptor Cereblon. Molecular cell 144 26990986
2009 Ubiquitin-mediated proteolysis of HuR by heat shock. The EMBO journal 142 19322201
2016 SPATA2-Mediated Binding of CYLD to HOIP Enables CYLD Recruitment to Signaling Complexes. Cell reports 115 27545878
2021 TopBP1 assembles nuclear condensates to switch on ATR signaling. Molecular cell 91 33503405
2021 SARS-CoV-2-host proteome interactions for antiviral drug discovery. Molecular systems biology 86 34709727
2016 Substrate-Trapped Interactors of PHD3 and FIH Cluster in Distinct Signaling Pathways. Cell reports 77 26972000
2018 Deubiquitinating enzyme PSMD14 promotes tumor metastasis through stabilizing SNAIL in human esophageal squamous cell carcinoma. Cancer letters 72 29331416
2021 Comprehensive interactome profiling of the human Hsp70 network highlights functional differentiation of J domains. Molecular cell 64 33957083
2019 PLEKHA4/kramer Attenuates Dishevelled Ubiquitination to Modulate Wnt and Planar Cell Polarity Signaling. Cell reports 42 31091453
2019 PRISMA: Protein Interaction Screen on Peptide Matrix Reveals Interaction Footprints and Modifications- Dependent Interactome of Intrinsically Disordered C/EBPβ. iScience 35 30884312
2016 TNIP2 is a Hub Protein in the NF-κB Network with Both Protein and RNA Mediated Interactions. Molecular & cellular proteomics : MCP 28 27609421
2020 SUMOylation of DDX39A Alters Binding and Export of Antiviral Transcripts to Control Innate Immunity. Journal of immunology (Baltimore, Md. : 1950) 27 32393512
2022 HSF1 phosphorylation establishes an active chromatin state via the TRRAP-TIP60 complex and promotes tumorigenesis. Nature communications 22 35906200
2022 EZH2 interacts with HP1BP3 to epigenetically activate WNT7B that promotes temozolomide resistance in glioblastoma. Oncogene 22 36517590
2022 Defining the proximal interaction networks of Arf GTPases reveals a mechanism for the regulation of PLD1 and PI4KB. The EMBO journal 21 35844135
2018 A Novel Loss-of-Function Variant in Transmembrane Protein 263 (TMEM263) of Autosomal Dwarfism in Chicken. Frontiers in genetics 18 29930570
2020 Epigenome-wide association study reveals a molecular signature of response to phylloquinone (vitamin K1) supplementation. Epigenetics 12 32090699
2020 Constructing a 10-core genes panel for diagnosis of pediatric sepsis. Journal of clinical laboratory analysis 12 33274532
2019 Identification of potassium channel proteins Kv7.2/7.3 as common partners of the dopamine and glutamate transporters DAT and GLT-1. Neuropharmacology 11 30885609
2024 Data-driven analysis that integrates bioinformatics and machine learning uncovers PANoptosis-related diagnostic genes in early pediatric septic shock. Heliyon 7 39315170
2021 TMEM263: a novel candidate gene implicated in human autosomal recessive severe lethal skeletal dysplasia. Human genomics 7 34238371
2024 Tmem263 deletion disrupts the GH/IGF-1 axis and causes dwarfism and impairs skeletal acquisition. eLife 3 38241182
2023 Tmem263 deletion disrupts the GH/IGF-1 axis and causes dwarfism and impairs skeletal acquisition. bioRxiv : the preprint server for biology 1 37577461
2024 Corrigendum: A novel loss-of-function variant in transmembrane protein 263 (TMEM263) of autosomal dwarfism in chicken. Frontiers in genetics 0 38259620