Affinage

DOP1B

Protein DOP1B · UniProt Q9Y3R5

Length
2298 aa
Mass
258.2 kDa
Annotated
2026-06-09
22 papers in source corpus 6 papers cited in narrative 6 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

DOP1B (DOPEY2/C21orf5) is a large leucine-zipper-like protein that controls endosomal retrograde trafficking and organelle positioning, with a deeply conserved role in tissue morphogenesis (PMID:10950924, PMID:30213940). It assembles into an evolutionarily conserved endosome-associated complex with MON2 and the putative aminophospholipid translocase ATP9A, and this complex is required for SNX3-retromer-mediated endosome-to-Golgi transport of Wntless; loss of the complex shunts Wntless to lysosomal degradation and disrupts Wnt signaling (PMID:30213940). DOPEY2 is recruited to recycling endosomes in a MON2-dependent manner and binds both kinesin and dynein/dynactin motors, so that its loss causes recycling endosomes to accumulate perinuclearly instead of distributing peripherally — placing DOPEY2 as a motor-coupled regulator of endosome positioning downstream of MON2 (PMID:32404555). Across organisms this trafficking function underlies developmental roles: the C. elegans ortholog pad-1 is essential for embryonic tissue patterning during gastrulation (PMID:10950924), and the zebrafish ortholog drives neural stem/progenitor proliferation, mutually restricting Pcdh7 expression to set brain size and architecture (PMID:36936789). A homozygous DOP1B variant segregates with autosomal recessive Peters anomaly in a consanguineous family, linking the gene to ocular developmental disease (PMID:33273802).

Mechanistic history

Synthesis pass · year-by-year structured walk · 6 steps
  1. 2000 Medium

    Established that the DOP1B ortholog is essential for development by showing its loss blocks embryonic tissue patterning, before any molecular function was known.

    Evidence RNAi knockdown of pad-1 in C. elegans with expression analysis

    PMID:10950924

    Open questions at the time
    • No molecular mechanism connecting the gene to patterning identified
    • Phenotype shown only in worm ortholog
  2. 2005 Low

    Defined DOP1B as a member of the Dopey leucine-zipper-like family with conserved C-terminal domains, framing a conserved morphogenesis function across phylogeny.

    Evidence Comparative sequence analysis and transgenic mouse overexpression with cortical cell density measurement

    PMID:16303751

    Open questions at the time
    • Leucine-zipper domain function not tested directly
    • Overexpression phenotype not mechanistically linked to trafficking
  3. 2018 High

    Resolved the molecular activity by showing DOPEY2 forms a trimeric complex with MON2 and ATP9A required for SNX3-retromer endosome-to-Golgi transport of Wntless, connecting the gene to Wnt signaling.

    Evidence Reciprocal Co-IP, in vivo C. elegans RNAi epistasis, and dominant-negative TAT-5(E246Q) overexpression

    PMID:30213940

    Open questions at the time
    • Stoichiometry and structural basis of the complex unresolved
    • Direct cargo set beyond Wntless not defined
    • Catalytic contribution of ATP9A translocase activity to DOPEY2 function unclear
  4. 2020 High

    Showed how DOPEY2 acts mechanically: it is recruited to recycling endosomes via MON2 and binds kinesin and dynein/dynactin motors to control endosome positioning.

    Evidence Live imaging, motor-protein Co-IP, and DOPEY2/MON2 knockout cell lines with organelle distribution readout

    PMID:32404555

    Open questions at the time
    • How DOPEY2 switches between opposing motors not defined
    • Link between positioning defect and retrograde cargo transport not directly tested
  5. 2023 Medium

    Extended the developmental role to vertebrate neurogenesis, showing Dopey2 drives neural stem/progenitor proliferation and reciprocally restricts Pcdh7 to shape brain size.

    Evidence Zebrafish genetic mutants with neural progenitor proliferation and expression epistasis assays

    PMID:36936789

    Open questions at the time
    • Mechanism linking endosomal trafficking to proliferation not established
    • Nature of Dopey2-Pcdh7 mutual restriction unknown
  6. 2020 Low

    Linked DOP1B to human disease by identifying a homozygous variant segregating with autosomal recessive Peters anomaly and localizing expression to ocular tissues.

    Evidence Exome sequencing with segregation analysis and RT-PCR in human eye tissues

    PMID:33273802

    Open questions at the time
    • No functional validation of the variant
    • Single consanguineous family
    • Trafficking mechanism linking gene to ocular phenotype untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How DOPEY2's endosomal trafficking and motor-coupling functions mechanistically produce its developmental and disease phenotypes remains unresolved.
  • No structural model of the DOPEY2-MON2-ATP9A complex
  • Cargo repertoire beyond Wntless undefined
  • Mechanistic bridge from trafficking to neural proliferation and ocular development missing

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 2 GO:0008092 cytoskeletal protein binding 1
Localization
GO:0005768 endosome 2
Pathway
R-HSA-1266738 Developmental Biology 2 R-HSA-5653656 Vesicle-mediated transport 2 R-HSA-9609507 Protein localization 1
Partners
ATP9AMON2
Complex memberships
DOPEY2-MON2-ATP9A complex

Evidence

Reading pass · 6 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 C21orf5 (DOP1B) ortholog in C. elegans (pad-1) is required for embryonic patterning: RNAi knockdown causes embryonic lethality with failure of tissue patterning during gastrulation and absence of morphogenesis, establishing an essential role in developmental patterning. Double-stranded RNA-mediated genetic interference (RNAi) in C. elegans; Northern blot; RNA in situ hybridization Genomics Medium 10950924
2005 C21orf5 (DOP1B) protein contains two highly conserved leucine-zipper-like domains at its C-terminus, placing it as a new member of the Dopey leucine zipper-like family (alongside Aspergillus nidulans DopA, S. cerevisiae Dop1, and C. elegans pad-1), with a conserved function in morphogenesis across phylogenesis. Comparative protein sequence analysis across species; transgenic mouse overexpression with in situ hybridization and real-time RT-PCR; cortical cell density measurement DNA research Low 16303751
2018 DOPEY2 forms an evolutionarily conserved endosome-associated complex with MON2 and the putative aminophospholipid translocase ATP9A; this complex is required for SNX3-retromer-mediated endosome-to-Golgi transport of Wntless, and in vivo suppression of C. elegans orthologs (Ce-mon-2, Ce-pad-1/DOPEY2, Ce-tat-5/ATP9A) phenocopies SNX3-retromer loss, causing enhanced lysosomal degradation of Wntless and a Wnt signaling phenotype. Co-immunoprecipitation; in vivo C. elegans RNAi suppression; ATPase-inhibited TAT-5(E246Q) mutant overexpression; biochemical fractionation; cell biology assays for Wntless trafficking Nature communications High 30213940
2020 Membrane-bound DOPEY2 is recruited to recycling endosomes (RE) dependent upon MON2 expression; DOPEY2 shows binding to kinesin and dynein/dynactin motor proteins; DOPEY2 knockout causes accumulation of RE at perinuclear regions rather than the peripheral distribution seen in wild-type cells, establishing DOPEY2 as a regulator of RE positioning/distribution downstream of MON2. Live imaging; biochemical co-immunoprecipitation (binding to motor proteins); DOPEY2 knockout cell lines; MON2 knockout cell lines; subcellular co-localization with RAB4B (RE marker) and SNX3 (EE marker) Cell structure and function High 32404555
2023 Dopey2 is responsible for the proliferation of neural stem cells/progenitors during embryonic neurogenesis in zebrafish; Dopey2 and Pcdh7 mutually restrict each other's expression, and loss of Dopey2 disrupts proper brain size and architecture. Zebrafish genetic mutants; proliferation assays of neural stem cells/progenitors; expression analysis of Dopey2 and Pcdh7 in mutant backgrounds iScience Medium 36936789
2020 A homozygous variant in DOP1B (p.Val1660 in a conserved residue) segregates with autosomal recessive Peters anomaly in a consanguineous family; DOP1B is expressed in lens, iris, cornea, sclera, and retina of human embryonic and adult eye tissues. Exome sequencing with variant segregation analysis; real-time PCR expression analysis in human ocular tissues Molecular vision Low 33273802

Source papers

Stage 0 corpus · 22 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2018 SNX3-retromer requires an evolutionary conserved MON2:DOPEY2:ATP9A complex to mediate Wntless sorting and Wnt secretion. Nature communications 71 30213940
2012 Analysis of copy number variation in Alzheimer's disease: the NIALOAD/ NCRAD Family Study. Current Alzheimer research 61 22486522
2021 CircRNA-DOPEY2 enhances the chemosensitivity of esophageal cancer cells by inhibiting CPEB4-mediated Mcl-1 translation. Journal of experimental & clinical cancer research : CR 52 34781999
2014 Functional transcriptome analysis of the postnatal brain of the Ts1Cje mouse model for Down syndrome reveals global disruption of interferon-related molecular networks. BMC genomics 51 25052193
2012 Analysis of copy number variation in Alzheimer's disease in a cohort of clinically characterized and neuropathologically verified individuals. PloS one 45 23227193
2000 C21orf5, a novel human chromosome 21 gene, has a Caenorhabditis elegans ortholog (pad-1) required for embryonic patterning. Genomics 19 10950924
2005 C21orf5, a new member of Dopey family involved in morphogenesis, could participate in neurological alterations and mental retardation in Down syndrome. DNA research : an international journal for rapid publication of reports on genes and genomes 18 16303751
2003 The differentially expressed C21orf5 gene in the medial temporal-lobe system could play a role in mental retardation in Down syndrome and transgenic mice. Biochemical and biophysical research communications 15 12767918
2020 MON2 Guides Wntless Transport to the Golgi through Recycling Endosomes. Cell structure and function 14 32404555
2006 C21orf5, a human candidate gene for brain abnormalities and mental retardation in Down syndrome. Cytogenetic and genome research 13 16276086
2020 Comparative accuracies of genetic values predicted for economically important milk traits, genome-wide association, and linkage disequilibrium patterns of Canadian Holstein cows. Journal of dairy science 12 33358789
2017 Properties of human genes guided by their enrichment in rare and common variants. Human mutation 12 29197136
2022 Indirect Immobilised Jagged-1 Enhances Matrisome Proteins Associated with Osteogenic Differentiation of Human Dental Pulp Stem Cells: A Proteomic Study. International journal of molecular sciences 9 36430375
2007 New cerebellar phenotypes in YAC transgenic mouse in vivo library of human Down syndrome critical region-1. Biochemical and biophysical research communications 9 17963726
2020 Autoimmune Mechanisms of Interferon Hypersensitivity and Neurodegenerative Diseases: Down Syndrome. Autoimmune diseases 5 32566271
2020 A mutation in DOP1B identified as a probable cause for autosomal recessive Peters anomaly in a consanguineous family. Molecular vision 5 33273802
2024 Real-World Clinical Utility of Targeted RNA Sequencing in Leukemia Diagnosis and Management. Cancers 3 39001529
2023 Dopey2 and Pcdh7 orchestrate the development of embryonic neural stem cells/ progenitors in zebrafish. iScience 3 36936789
2024 Revisiting the impact of genomic hot spots: C12orf35 locus as a hot spot and engineering target. Biotechnology and bioengineering 2 38978356
2026 Real-world-data for phenotypes and genotypes of rare monogenic genetic epilepsies and genes of uncertain significance for epilepsy. Epilepsia open 0 42220229
2024 A genetic investigation in five Chinese families with keratoconus. PeerJ 0 39238827
2005 [Cell-cycle negative regulatory gene ANA is over-expressed in the brain tissues of patients with Down syndrome]. Beijing da xue xue bao. Yi xue ban = Journal of Peking University. Health sciences 0 16378112

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