Affinage

RTTN

Rotatin · UniProt Q86VV8

Length
2226 aa
Mass
248.6 kDa
Annotated
2026-06-10
16 papers in source corpus 5 papers cited in narrative 5 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RTTN (Rotatin) is a centriolar protein that governs centriole assembly and elongation and, through this role, controls mitotic fidelity and the polarization of neural stem cells during cortical development (PMID:28811500, PMID:39680576). Recruited to the proximal end of the procentriole in early S phase and residing at the inner luminal walls of centrioles, RTTN directly binds STIL and acts downstream of STIL-mediated centriole assembly; its loss generates amplified primitive procentriole bodies that lack the distal-half centriolar proteins POC5 and POC1B because RTTN functions as an upstream effector of CEP295-mediated loading of these proteins (PMID:28811500). RTTN further forms a complex with PPP1R35, positioning it within a distal centriole elongation pathway in which PPP1R35 acts downstream of RTTN (PMID:30168418). The microcephaly-associated RTTN(A578P) mutant has reduced STIL affinity and blocks centriole assembly, linking the molecular pathway to disease (PMID:28811500). Beyond centriole biogenesis, RTTN is required for correct mitotic spindle positioning, regulating NuMA/p150Glued congression and cortical localization and maintaining astral microtubule number and length (PMID:34207628), and its loss in neural stem cells and cortical organoids causes aneuploidy, cell death, and delayed apico-basal polarization with failed neural rosette self-organization (PMID:39680576). RTTN also localizes to basal bodies of the primary cilium, where it is needed for cilia structure and normal BMP/WNT signaling (PMID:22939636).

Mechanistic history

Synthesis pass · year-by-year structured walk · 5 steps
  1. 2012 Medium

    Established the first cellular role for RTTN by linking it to ciliary structure and developmental signaling, addressing why RTTN mutations cause human disease.

    Evidence Immunofluorescence colocalization at basal bodies plus knockdown in patient fibroblasts and neural stem cells with BMP/WNT expression readouts

    PMID:22939636

    Open questions at the time
    • Did not define a molecular partner or biochemical activity
    • Mechanism connecting RTTN to BMP/WNT downregulation unresolved
  2. 2017 High

    Defined RTTN's molecular position in centriole biogenesis, answering how it contributes to centriole assembly: it binds STIL and licenses distal centriole maturation via CEP295.

    Evidence Super-resolution/EM localization, CRISPR knockout, direct STIL interaction assay, and the A578P disease mutant in human cells

    PMID:28811500

    Open questions at the time
    • Structural basis of the RTTN-STIL interaction not resolved
    • How RTTN promotes CEP295-mediated POC1B/POC5 loading mechanistically unclear
  3. 2018 High

    Extended the elongation pathway by placing PPP1R35 downstream of RTTN in a shared complex, clarifying how distal centriole elongation is executed.

    Evidence Quantitative super-resolution microscopy, live-cell imaging, and Co-IP complex formation with PPP1R35 depletion phenotyping

    PMID:30168418

    Open questions at the time
    • Stoichiometry and architecture of the RTTN-PPP1R35 complex unknown
    • Whether PPP1R35 phosphatase regulatory activity is involved not addressed
  4. 2021 Medium

    Showed RTTN's centriolar role propagates to mitotic spindle control, explaining how its loss disrupts division through NuMA/p150Glued and astral microtubule defects.

    Evidence siRNA depletion with immunofluorescence and spindle positioning assays scoring spindle morphology and cortical NuMA

    PMID:34207628

    Open questions at the time
    • Direct versus indirect effect on NuMA cortical localization not distinguished
    • No physical interaction with spindle factors demonstrated
  5. 2024 Medium

    Connected RTTN's centrosomal function to neurodevelopmental outcome, demonstrating that its loss drives aneuploidy and impaired neural stem cell polarization in organoid models of cortical development.

    Evidence CRISPR-edited iPSC-derived neural stem cells and cortical organoids with cell cycle analysis and immunofluorescence, plus patient fibroblasts

    PMID:39680576

    Open questions at the time
    • Molecular link between centriole defect and apico-basal polarization not defined
    • Single-lab organoid models

Open questions

Synthesis pass · forward-looking unresolved questions
  • How RTTN structurally engages STIL, CEP295 and PPP1R35 to coordinate distal centriole elongation, and whether its biochemical activity is enzymatic or purely scaffolding, remains unresolved.
  • No structural model of RTTN or its complexes
  • No defined catalytic activity for RTTN
  • Mechanism coupling centriole defects to ciliary BMP/WNT signaling unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 2
Localization
GO:0005815 microtubule organizing center 1 GO:0005929 cilium 1
Pathway
R-HSA-1640170 Cell Cycle 2 R-HSA-1852241 Organelle biogenesis and maintenance 2 R-HSA-1266738 Developmental Biology 1
Partners
CEP295PPP1R35STIL
Complex memberships
RTTN-PPP1R35 complex

Evidence

Reading pass · 5 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2012 RTTN (Rotatin) colocalizes with basal bodies at the primary cilium. Cultured fibroblasts from affected individuals carrying RTTN mutations show structural abnormalities of cilia and exhibit downregulation of BMP4, WNT5A, and WNT2B. Knockdown of RTTN in human fibroblasts and neural stem cells confirmed a role for RTTN in cilia structure and function. Immunofluorescence colocalization, knockdown experiments in human fibroblasts and neural stem cells, gene expression analysis American journal of human genetics Medium 22939636
2017 RTTN is recruited to the proximal end of the procentriole at early S phase and is located at the inner luminal walls of centrioles. RTTN directly interacts with STIL and acts downstream of STIL-mediated centriole assembly. CRISPR/Cas9-mediated RTTN knockout induces amplification of primitive procentriole bodies lacking distal-half centriolar proteins POC5 and POC1B. RTTN serves as an upstream effector of CEP295, which mediates loading of POC1B and POC5 to distal-half centrioles. The microcephaly-associated mutant RTTN(A578P) shows low affinity for STIL binding and blocks centriole assembly. Super-resolution and electron microscopy, CRISPR/Cas9 knockout, Co-IP/direct interaction assays, active-site mutagenesis (A578P mutant), immunofluorescence Nature communications High 28811500
2018 PPP1R35 acts downstream of RTTN and forms a complex with RTTN in the centriole elongation pathway. Loss of PPP1R35 results in shortened centrioles lacking distal and microtubule wall-associated proteins. RTTN is required for distal centriole elongation, and PPP1R35 is positioned proximal to the cartwheel, downstream of RTTN. Quantitative super-resolution microscopy, live-cell imaging, Co-IP/complex formation assay, loss-of-function (PPP1R35 depletion) with defined centriolar phenotype eLife High 30168418
2021 RTTN is required for normal mitotic progression and correct spindle positioning. Depletion of RTTN induces dispersion of pericentriolar γ-tubulin, and multiple mitotic abnormalities including monopolar, abnormal bipolar, and multipolar spindles. Loss of RTTN alters NuMA/p150Glued congression to spindle poles, perturbs NuMA cortical localization, and reduces the number and length of astral microtubules. siRNA depletion, immunofluorescence microscopy, spindle positioning assay Cells Medium 34207628
2024 In RTTN-depleted RPE1 cells and patient fibroblasts carrying the c.2953A>G variant, RTTN function at the centrosome is disrupted. In neural stem cells derived from CRISPR/Cas9-edited iPSCs, RTTN loss causes major cell cycle and mitotic abnormalities leading to aneuploidy, cell cycle arrest, and cell death. In cortical organoids, RTTN is required for self-organisation of neural stem cells into neural rosettes, with loss causing delayed apico-basal polarization of neural stem cells. CRISPR/Cas9 gene editing, iPSC-derived neural stem cells and cortical organoids, immunofluorescence, cell cycle analysis PLoS genetics Medium 39680576

Source papers

Stage 0 corpus · 16 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 RTTN mutations link primary cilia function to organization of the human cerebral cortex. American journal of human genetics 58 22939636
2017 Human microcephaly protein RTTN interacts with STIL and is required to build full-length centrioles. Nature communications 39 28811500
2015 RTTN Mutations Cause Primary Microcephaly and Primordial Dwarfism in Humans. American journal of human genetics 38 26608784
2018 PPP1R35 is a novel centrosomal protein that regulates centriole length in concert with the microcephaly protein RTTN. eLife 29 30168418
2016 Expanding the phenotype of RTTN variations: a new family with primary microcephaly, severe growth failure, brain malformations and dermatitis. Clinical genetics 21 26940245
2018 Recurrent RTTN mutation leading to severe microcephaly, polymicrogyria and growth restriction. European journal of medical genetics 13 30121372
2018 Biallelic mutations in RTTN are associated with microcephaly, short stature and a wide range of brain malformations. European journal of medical genetics 11 29883675
2021 Human Microcephaly Protein RTTN Is Required for Proper Mitotic Progression and Correct Spindle Position. Cells 8 34207628
2018 A neuropathological study of novel RTTN gene mutations causing a familial microcephaly with simplified gyral pattern. Birth defects research 8 29356416
2023 Microcephaly, Short Stature, Intellectual Disability, Speech Absence and Cataract Are Associated with Novel Bi-Allelic Missense Variant in RTTN Gene: A Seckel Syndrome Case Report. Children (Basel, Switzerland) 7 37371259
2021 Exome sequencing reveled a compound heterozygous mutations in RTTN gene causing developmental delay and primary microcephaly. Saudi journal of biological sciences 6 34012324
2024 A Taybi-Linder syndrome-related RTTN variant impedes neural rosette formation in human cortical organoids. PLoS genetics 3 39680576
2019 Primary microcephaly, primordial dwarfism, and brachydactyly in adult cases with biallelic skipping of RTTN exon 42. Human mutation 3 30927481
2025 Radial Microbrain (Micrencephaly) Is Caused by a Recurrent Variant in the RTTN Gene. Neurology. Genetics 1 40151166
2023 Case Report: Novel biallelic moderately damaging variants in RTTN in a patient with cerebellar dysplasia. Frontiers in pediatrics 1 38178912
2026 Generation of the iPSC line CRNLi001-A from a patient with microcephaly and harbouring the most recurrent RTTN variant, c.2953A>G, at homozygous state. Stem cell research 0 41719742

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