Affinage

SDCCAG8

Serologically defined colon cancer antigen 8 · UniProt Q86SQ7

Length
713 aa
Mass
82.7 kDa
Annotated
2026-04-28
17 papers in source corpus 12 papers cited in narrative 12 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SDCCAG8 is a centrosomal and basal body protein essential for ciliogenesis, centriolar satellite integrity, and cilium-dependent signaling across multiple tissue types. Its C-terminal coiled-coil domains mediate centrosomal targeting, homo-oligomerization, and direct interactions with ICK/CILK1, MAK, and the centriolar satellite scaffold protein PCM1, through which it recruits pericentriolar material (γ-tubulin, pericentrin) and satellite components (BBS4, CEP131) required for cilium and sperm flagellum assembly (PMID:12559564, PMID:25088364, PMID:35131266, PMID:40801568). Loss of SDCCAG8 disrupts primary cilia formation, Hedgehog signaling, ciliary trafficking of photoreceptor proteins (rhodopsin, RPGR), centrosome–nucleus coupling during neuronal migration, and activates aberrant ATM-dependent DNA damage response signaling (PMID:24722439, PMID:27224062, PMID:31868218). Biallelic mutations in SDCCAG8 cause a multi-organ ciliopathy in mice and humans characterized by retinal degeneration, cystic kidneys, polydactyly, cleft palate, and male infertility (PMID:20835237, PMID:35131266, PMID:35503560).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2003 Medium

    Establishing that SDCCAG8 is an integral centrosomal protein whose coiled-coil domains are required for centrosomal localization and self-association resolved its subcellular identity as a core centrosome component rather than a microtubule-associated protein.

    Evidence Immunofluorescence with nocodazole treatment, yeast two-hybrid, and truncation mutagenesis in cultured cells

    PMID:12559564

    Open questions at the time
    • No interaction partners beyond self-association identified
    • No functional consequence of centrosomal loss assessed
    • Single lab, not independently replicated at this time
  2. 2010 High

    Demonstrating that SDCCAG8 interacts with the ciliopathy protein OFD1 and that its depletion causes kidney cysts and body-axis defects in zebrafish established SDCCAG8 as a ciliopathy gene required for renal and planar cell polarity.

    Evidence Co-immunoprecipitation, zebrafish morpholino knockdown, 3D renal cell culture

    PMID:20835237

    Open questions at the time
    • Mechanism by which SDCCAG8 loss leads to cystogenesis undefined
    • No mammalian loss-of-function model yet
  3. 2012 Medium

    Showing that RPGRIP1 is required for SDCCAG8 ciliary targeting specifically in photoreceptors but not kidney cells revealed cell-type-specific regulation of SDCCAG8 localization.

    Evidence Rpgrip1 mutant mouse, immunofluorescence, subcellular fractionation

    PMID:22825473

    Open questions at the time
    • Molecular basis of RPGRIP1-dependent targeting not defined
    • Whether other cell types use analogous adaptors unknown
    • Single lab study
  4. 2014 High

    Two concurrent studies showed that SDCCAG8 recruits pericentriolar material and PCM1 to centrosomes for neuronal migration, and that its loss activates ATM-dependent DNA damage signaling alongside retinal and renal pathology, broadening its function beyond ciliogenesis to centrosome–nucleus coupling and genome maintenance.

    Evidence Sdccag8 gene-trap mouse, shRNA knockdown in cortex, co-immunoprecipitation of SDCCAG8–PCM1, γH2AX/pATM immunoblotting, flow cytometry

    PMID:24722439 PMID:25088364

    Open questions at the time
    • Whether DNA damage response activation is direct or secondary to ciliary/centrosomal dysfunction unclear
    • Mechanism linking PCM1 co-trafficking to pericentriolar material recruitment not resolved
  5. 2016 High

    Affinity proteomics expanded the SDCCAG8 interactome to include endosomal sorting proteins (RABEP2, ERC1) and non-muscle myosins, and demonstrated that SDCCAG8 is required for Hedgehog signaling, linking it to cilium-dependent morphogen pathways.

    Evidence Tandem affinity purification/mass spectrometry, siRNA knockdown, Sdccag8 gene-trap mouse, Hedgehog reporter assays

    PMID:27224062

    Open questions at the time
    • Functional significance of RABEP2 and myosin interactions for ciliogenesis untested
    • Hedgehog signaling rescue not demonstrated
  6. 2020 Medium

    CRISPR-mediated knockout in human cells confirmed SDCCAG8's cell-autonomous requirement for ciliogenesis, cilium-dependent signaling, and neuronal migration/differentiation, validating prior knockdown findings in a human context.

    Evidence CRISPR knockout in human cells, immunofluorescence, transcriptomics, neuronal differentiation assays

    PMID:31868218

    Open questions at the time
    • Specific signaling pathways downstream of ciliary loss not fully dissected
    • Single lab
  7. 2022 High

    Precise C-terminal truncation in knock-in mice pinpointed the C-terminal coiled-coil region as the domain mediating interactions with ciliopathy kinases ICK/CILK1 and MAK and as essential for centrosomal localization, cilia formation, and prevention of multi-organ ciliopathy phenotypes.

    Evidence CRISPR knock-in truncation mouse models, co-immunoprecipitation with ICK and MAK, electron microscopy, immunofluorescence

    PMID:35131266 PMID:35503560

    Open questions at the time
    • Whether ICK/MAK phosphorylate SDCCAG8 directly unknown
    • Structural basis of C-terminal domain interactions not determined
  8. 2025 High

    Mapping SDCCAG8's coiled-coil domains 5–7 as the PCM1-binding interface and showing that their loss destabilizes centriolar satellite proteins BBS4 and CEP131, causing defective sperm flagellum biogenesis, established a molecular mechanism linking SDCCAG8 to satellite integrity and male fertility.

    Evidence CC-domain truncation knock-in mouse, co-immunoprecipitation of SDCCAG8–PCM1 domain mapping, immunofluorescence for satellite markers, electron microscopy of flagella

    PMID:40801568

    Open questions at the time
    • Whether satellite destabilization fully accounts for all ciliopathy phenotypes not tested
    • Direct stoichiometry or structure of SDCCAG8–PCM1 complex unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis of SDCCAG8's interactions with PCM1, ICK/MAK, and OFD1; whether the DNA damage response phenotype is a direct function or secondary to centrosomal/ciliary defects; and the full spectrum of ciliary cargo whose trafficking depends on SDCCAG8.
  • No atomic-resolution structural data for SDCCAG8 or its complexes
  • DNA damage response mechanism not separated from ciliary dysfunction
  • Complete inventory of SDCCAG8-dependent ciliary cargo lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 3 GO:0008092 cytoskeletal protein binding 2
Localization
GO:0005815 microtubule organizing center 6 GO:0005929 cilium 5 GO:0005856 cytoskeleton 2
Pathway
R-HSA-1852241 Organelle biogenesis and maintenance 6 R-HSA-1266738 Developmental Biology 2 R-HSA-162582 Signal Transduction 2 R-HSA-73894 DNA Repair 1
Partners
BBS4CEP131ICKMAKOFD1PCM1RABEP2RPGRIP1
Complex memberships
centriolar satellites (PCM1/BBS4/CEP131)

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 SDCCAG8 (CCCAP) localizes to centrosomes during both interphase and mitosis, is resistant to nocodazole-induced microtubule depolymerization (indicating it is an integral centrosomal component rather than a microtubule-associated protein), and its C-terminal coiled-coil domain mediates homo-oligomerization as demonstrated by yeast two-hybrid. N- and C-terminal truncations abolish centrosomal localization. Immunofluorescence localization, nocodazole treatment, yeast two-hybrid, truncation mutagenesis Gene Medium 12559564
2010 SDCCAG8 localizes at both centrioles and directly interacts with OFD1 (oral-facial-digital syndrome 1 protein). Depletion of sdccag8 in zebrafish causes kidney cysts and body axis defects, and induces cell polarity defects in 3D renal cell cultures. Immunofluorescence, direct protein interaction assay (co-immunoprecipitation/pulldown), zebrafish morpholino knockdown, 3D renal cell culture Nature genetics High 20835237
2012 RPGRIP1 is required for ciliary targeting of SDCCAG8 in photoreceptor neurons; loss of RPGRIP1 expression shifts SDCCAG8 subcellular partitioning to the endoplasmic reticulum membrane fraction and strongly decreases its ciliary localization in photoreceptors but not in kidney cells, revealing cell type-dependent regulation of SDCCAG8 ciliary targeting. Immunofluorescence, subcellular fractionation, Rpgrip1 mutant mouse model Cell death & disease Medium 22825473
2014 Loss of Sdccag8 in a mouse gene-trap model causes retinal degeneration with rhodopsin mislocalization in photoreceptors, and renal pathology associated with elevated DNA damage response signaling (elevated γH2AX and phosphorylated ATM). Cell culture studies confirmed aberrant activation of ATM-dependent DNA damage response signaling and cell cycle profile abnormalities in Sdccag8-deficient cells. Sdccag8 gene-trap mouse model, immunofluorescence, western blotting (γH2AX, pATM), flow cytometry cell cycle analysis Journal of the American Society of Nephrology High 24722439
2014 SDCCAG8 regulates centrosomal accumulation of pericentriolar material (γ-tubulin and pericentrin), microtubule organization, centrosome-nucleus coupling, and neuronal migration in the developing cortex. SDCCAG8 interacts and co-traffics with PCM1 (pericentriolar material 1), a centriolar satellite protein required for centrosomal protein targeting. shRNA knockdown, loss-of-function allele in mouse cortex, immunofluorescence, co-immunoprecipitation (SDCCAG8–PCM1 interaction), live imaging Neuron High 25088364
2016 SDCCAG8 interacts with centriolar satellite proteins OFD1 and AZI1, endosomal sorting complex proteins RABEP2 and ERC1, and non-muscle myosin motor proteins MYH9, MYH10, and MYH14 at the centrosome, as identified by affinity proteomics. SDCCAG8 regulates centrosomal localization of RABEP2, and SDCCAG8 is required for ciliogenesis and Hedgehog signaling. Affinity proteomics/mass spectrometry, co-immunoprecipitation, siRNA knockdown, immunofluorescence, Sdccag8 gene-trap mouse model PloS one High 27224062
2019 SOX11 transcription factor directly binds the SDCCAG8 gene promoter and transcriptionally activates SDCCAG8 expression; wild-type but not DNA-binding mutant SOX11 induces SDCCAG8 promoter activity. SDCCAG8 mediates pro-tumorigenic effects of SOX11 on HNSCC cell proliferation, migration, and invasion. Chromatin immunoprecipitation (ChIP), luciferase reporter assay, rescue assay, SOX11 mutant overexpression Journal of experimental & clinical cancer research Medium 30922366
2020 Genome editing-mediated loss of SDCCAG8 causes defects in primary ciliogenesis and cilium-dependent cell signaling, and impairs neuronal cell migration and differentiation. Genome editing (CRISPR), immunofluorescence for cilia, transcriptomic analysis, neuronal migration/differentiation assays Human molecular genetics Medium 31868218
2022 The C-terminal region of SDCCAG8 (Sdccag8-C) is essential for its localization to centrosomes and cilia formation. Sdccag8-C interacts with ciliopathy kinases ICK/CILK1 and MAK, which regulate ciliary protein trafficking and cilia length. Truncation of Sdccag8-C in mice causes cilia formation defects and ciliopathy-like phenotypes including cleft palate, polydactyly, retinal degeneration, cystic kidney, and spermatogenesis defects. CRISPR knock-in truncation mouse model, co-immunoprecipitation (Sdccag8-C with ICK/CILK1 and MAK), immunofluorescence for centrosomal localization and cilia The Journal of biological chemistry High 35131266
2022 Hypomorphic Sdccag8 truncation mutations in knock-in mice cause defective cilia in photoreceptors, renal epithelial cells, and mouse embryonic fibroblasts, with major phototransduction protein mislocalization outside outer segments, confirming SDCCAG8's essential role in ciliogenesis as a primary driver of retinal ciliopathy pathology. CRISPR/Cas9 knock-in mouse models, electron microscopy, immunofluorescence for cilia and phototransduction proteins Zoological research Medium 35503560
2025 SDCCAG8 protein localizes to the sperm manchette and centrosomal region and interacts with PCM1 (the centriolar satellite scaffold protein) through its coiled-coil domains 5–7. Loss of CC domains 5–8 destabilizes PCM1 and prevents recruitment of BBS4 and CEP131 to centriolar satellites, causing defective sperm flagellum biogenesis and male infertility (MMAF phenotype). Sdccag8 CC-domain truncation knock-in mouse, co-immunoprecipitation (SDCCAG8–PCM1), immunofluorescence for PCM1/BBS4/CEP131 at satellites, electron microscopy of flagella Cells High 40801568
2025 Intronic mutations in SDCCAG8 cause cryptic exon inclusion with premature termination codons and loss of SDCCAG8 protein; antisense oligonucleotides targeting the cryptic exon splice sites restore correct exon 7–8 splicing and rescue SDCCAG8 protein expression to ~40% of wild-type in patient-derived fibroblasts. RT-PCR splicing assay, RNA sequencing, western blotting; ASO-mediated splice-switching in patient fibroblasts bioRxivpreprint Medium 41279107

Source papers

Stage 0 corpus · 17 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 Candidate exome capture identifies mutation of SDCCAG8 as the cause of a retinal-renal ciliopathy. Nature genetics 269 20835237
2011 Mutations in SDCCAG8/NPHP10 Cause Bardet-Biedl Syndrome and Are Associated with Penetrant Renal Disease and Absent Polydactyly. Molecular syndromology 67 22190896
2014 Renal-retinal ciliopathy gene Sdccag8 regulates DNA damage response signaling. Journal of the American Society of Nephrology : JASN 61 24722439
2014 SDCCAG8 regulates pericentriolar material recruitment and neuronal migration in the developing cortex. Neuron 46 25088364
2012 Selective loss of RPGRIP1-dependent ciliary targeting of NPHP4, RPGR and SDCCAG8 underlies the degeneration of photoreceptor neurons. Cell death & disease 41 22825473
2019 Sox11 promotes head and neck cancer progression via the regulation of SDCCAG8. Journal of experimental & clinical cancer research : CR 30 30922366
2003 Identification and characterization of the novel centrosome-associated protein CCCAP. Gene 25 12559564
2016 SDCCAG8 Interacts with RAB Effector Proteins RABEP2 and ERC1 and Is Required for Hedgehog Signaling. PloS one 23 27224062
2022 The carboxyl-terminal region of SDCCAG8 comprises a functional module essential for cilia formation as well as organ development and homeostasis. The Journal of biological chemistry 14 35131266
2020 Altered gene regulation as a candidate mechanism by which ciliopathy gene SDCCAG8 contributes to schizophrenia and cognitive function. Human molecular genetics 12 31868218
2020 A novel splice site mutation in the SDCCAG8 gene in an Iranian family with Bardet-Biedl syndrome. International ophthalmology 6 32926352
2019 Rapidly Progressive Nephronophthisis in a 2-Year-Old Boy with a Homozygous SDCCAG8 Mutation. The Tohoku journal of experimental medicine 5 31534065
2022 Characterization of two novel knock-in mouse models of syndromic retinal ciliopathy carrying hypomorphic Sdccag8 mutations. Zoological research 4 35503560
2025 Loss of C-Terminal Coiled-Coil Domains in SDCCAG8 Impairs Centriolar Satellites and Causes Defective Sperm Flagellum Biogenesis and Male Fertility. Cells 2 40801568
2022 Locally advanced undifferentiated small round cell sarcoma of the lung with novel SDCCAG8-AKT3 fusion and type II tumor immunity in the microenvironment: a rare case report. Translational lung cancer research 2 36090644
2021 Genetic variants of SDCCAG8 and MAGI2 in mitosis-related pathway genes are independent predictors of cutaneous melanoma-specific survival. Cancer science 2 34375487
2025 Splice-switching antisense oligonucleotides correct cryptic exon inclusion and restore SDCCAG8 protein in Bardet-Biedl Syndrome. bioRxiv : the preprint server for biology 0 41279107