Affinage

SPATA7

Spermatogenesis-associated protein 7 · UniProt Q9P0W8

Length
599 aa
Mass
67.7 kDa
Annotated
2026-06-10
34 papers in source corpus 9 papers cited in narrative 9 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

SPATA7 is a ciliary scaffold protein essential for the structural integrity and protein composition of the photoreceptor connecting cilium, where its loss causes progressive rod and cone degeneration (PMID:25398945, PMID:29100828). It localizes to the connecting cilium and primary cilium and directly interacts with RPGRIP1; in Spata7-null photoreceptors RPGRIP1 is depleted from the connecting cilium, rhodopsin accumulates in the inner segments and perinuclear region rather than trafficking to outer segments, and rod photoreceptors undergo apoptosis (PMID:25398945). Super-resolution imaging resolves SPATA7's action to the distal connecting cilium (DCC), a photoreceptor-specific extension distinct from the transition-zone-equivalent proximal connecting cilium, where it maintains photoreceptor-specific DCC proteins including RPGR and RPGRIP1; its absence mislocalizes DCC proteins, destabilizes axonemal microtubules, and degenerates photoreceptors without disrupting the proximal zone (PMID:29899041). SPATA7 function is required cell-autonomously in photoreceptors and not in the RPE (PMID:29100828), and it is needed not only to build the connecting cilium but to maintain it in the adult retina, where inducible loss shortens the cilium, mislocalizes rhodopsin, and triggers ER stress-mediated apoptosis (PMID:35368022). AAV-mediated SPATA7 gene replacement in knockout mice restores correct localization, improves photoresponse and ultrastructure, and slows degeneration (PMID:25965394). An earlier biochemical line of work characterized the protein in germ cells, where it binds GTP, has GTPase activity, is phosphorylated by PKC, localizes to spermatozoa and pachytene spermatocytes, and activates ERK1/2 through a GDP-dependent interaction with the Gβ1 subunit requiring its TPR and P-loop domains (PMID:11517287, PMID:16368546).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2001 Medium

    Initial biochemical characterization asked what kind of protein SPATA7 (HSD-3.8) is, establishing it as a TPR- and P-loop-containing GTP-binding protein expressed in germ cells.

    Evidence Recombinant protein GTP-binding overlay, GTPase and in vitro PKC phosphorylation assays, immunostaining of human testis and spermatozoa

    PMID:11517287

    Open questions at the time
    • Biochemical activities shown in vitro only, not in a physiological context
    • No connection yet to ciliary biology or photoreceptors
    • GTPase activity not linked to a downstream effector
  2. 2002 Low

    A binding partner was sought to place SPATA7 in a signaling context, identifying the Gβ1 subunit C-terminus as an interactor.

    Evidence Yeast two-hybrid screen of human ovary cDNA library with truncation analysis

    PMID:12905684

    Open questions at the time
    • Yeast two-hybrid only, no in-cell validation in this study
    • Functional consequence of the interaction not addressed
    • Physiological relevance unknown
  3. 2006 Medium

    The Gβ1 interaction was validated in cells and linked to a downstream pathway, establishing a domain-dependent route to ERK1/2 activation.

    Evidence Co-IP and colocalization in HEK293 cells plus ERK1/2 activation assays with TPR- and P-loop-deletion mutants

    PMID:16368546

    Open questions at the time
    • Demonstrated by overexpression in HEK293, not endogenous setting
    • Single lab, no independent replication
    • Relevance to photoreceptor function not established
  4. 2014 High

    The first photoreceptor study redefined SPATA7 as a ciliary protein, showing it scaffolds RPGRIP1 at the connecting cilium and is needed for rhodopsin trafficking and photoreceptor survival.

    Evidence Immunolocalization, direct interaction assay, Spata7-null mouse with histology, immunofluorescence and ERG

    PMID:25398945

    Open questions at the time
    • Sub-ciliary zone of action not resolved
    • Mechanism of RPGRIP1 stabilization not defined
    • Connection to earlier germ-cell GTPase activity not reconciled
  5. 2017 High

    Cell-type-specific knockouts asked where SPATA7 is required, establishing a cell-autonomous photoreceptor requirement and excluding the RPE.

    Evidence Crx-Cre and Best1-Cre conditional knockout mice with histology, immunofluorescence and ERG

    PMID:29100828

    Open questions at the time
    • Does not distinguish developmental from maintenance roles
    • Molecular basis of rhodopsin mislocalization unresolved
  6. 2018 High

    Super-resolution imaging localized SPATA7's action to the distal connecting cilium, defining a photoreceptor-specific ciliary sub-compartment it maintains together with RPGR and RPGRIP1.

    Evidence STORM super-resolution imaging across multiple genetic mouse models with immunofluorescence

    PMID:29899041

    Open questions at the time
    • Mechanism by which SPATA7 partitions DCC from PCC unknown
    • How DCC protein retention stabilizes axonemal microtubules not defined
  7. 2022 High

    Inducible adult knockout separated maintenance from development, showing SPATA7 is continuously required to preserve the mature connecting cilium and that its loss triggers ER stress-mediated apoptosis.

    Evidence Tamoxifen-inducible adult-stage Spata7 knockout with histology, immunofluorescence, ERG and ER stress markers

    PMID:35368022

    Open questions at the time
    • Link between ciliary collapse and the ER stress response not mechanistically traced
    • Single lab
  8. 2025 Medium

    A natural canine model confirmed SPATA7 as the causal cone-rod dystrophy gene and localized it to the transition zone region, excluding the neighboring PTPN21 gene.

    Evidence GWAS, homozygosity mapping, U-ExM imaging in dog tissues, and Ptpn21 knockout mouse phenotyping

    PMID:41325489

    Open questions at the time
    • Functional consequence of the C-terminal truncation not directly tested
    • Single lab, natural animal model

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the germ-cell GTPase/Gβ1/ERK signaling activity of SPATA7 relates to its ciliary scaffolding role in photoreceptors remains unresolved.
  • No study connects the in vitro GTP-binding/PKC/ERK activities to ciliary function
  • No structural model of how TPR and P-loop domains engage RPGRIP1/RPGR
  • Mechanism of RPGRIP1 stabilization at the DCC undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 2 GO:0003924 GTPase activity 1
Localization
GO:0005929 cilium 3 GO:0005829 cytosol 1
Pathway
R-HSA-1852241 Organelle biogenesis and maintenance 3 R-HSA-9709957 Sensory Perception 2
Partners
GNB1RPGRRPGRIP1

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2014 SPATA7 localizes at the primary cilium of cells and at the connecting cilium (CC) of photoreceptor cells, and directly interacts with RPGRIP1. In Spata7 null mutant mice, RPGRIP1 levels at the CC are substantially reduced, indicating SPATA7 is required for stable assembly and localization of the ciliary RPGRIP1 protein complex. Loss of Spata7 also causes rhodopsin accumulation in inner segments and around nuclei of photoreceptors, indicating a role in protein trafficking across the CC to outer segments, and triggers apoptosis of rod photoreceptors. Immunolocalization, co-immunoprecipitation/direct interaction assay, Spata7 null mouse model with histology and immunofluorescence, electroretinography Human molecular genetics High 25398945
2018 The photoreceptor connecting cilium (CC) can be partitioned into a proximal CC (PCC), homologous to the transition zone of primary cilia, and a distal CC (DCC), a photoreceptor-specific extension. SPATA7 specifically maintains the DCC zone and interacts with photoreceptor-specific ciliary proteins RPGR and RPGRIP1. Absence of Spata7 causes mislocalization of DCC proteins without affecting PCC protein complexes, leading to destabilization of axonemal microtubules and photoreceptor degeneration. Stochastic optical reconstruction microscopy (STORM) super-resolution imaging in multiple genetic models, immunofluorescence, genetic mouse models The Journal of cell biology High 29899041
2017 Conditional knockout of Spata7 specifically in photoreceptors (using Crx-Cre) causes rod and cone photoreceptor dysfunction and degeneration with progressive outer nuclear layer thinning and reduced ERG response, along with mislocalization of Rhodopsin and RPGRIP1 in the connecting cilium. RPE-specific deletion of Spata7 (Best1-Cre) does not impair retinal function or cell survival. Thus, SPATA7 function is required in photoreceptors but not in RPE for photoreceptor survival. Conditional (cell-type-specific) knockout mouse models (Crx-Cre and Best1-Cre), histology, immunofluorescence, electroretinography Experimental eye research High 29100828
2022 SPATA7 is required not only for the initial establishment but also for the maintenance of the mature retinal connecting cilium (CC). Inducible adult-specific Spata7 knockout (tamoxifen-induced Spata7flox/-; UbcCreERT2/+) causes photoreceptor degeneration, defective ERG, significantly shortened NPHP1 length at the CC, mislocalization of rhodopsin, and ER stress-mediated apoptosis. Inducible adult-stage knockout mouse model, histology, immunofluorescence, electroretinography, ER stress markers Scientific reports High 35368022
2015 AAV8(Y733F)-mediated delivery of FLAG-tagged Spata7 cDNA driven by hGRK1 to photoreceptors in Spata7 knockout mice results in colocalization of delivered SPATA7 with endogenous SPATA7 localization pattern, improvement of photoresponse, improved photoreceptor ultrastructure, and significant alleviation of photoreceptor degeneration when treated at P15, P28, or P56. Long-term treatment ameliorates rod and cone loss but does not fully prevent progressive degeneration by 86 weeks. Subretinal AAV injection in Spata7 knockout mouse model, electroretinography, histology, immunofluorescence Gene therapy Medium 25965394
2001 The protein encoded by HSD-3.8 (SPATA7) contains a tetratricopeptide repeat (TPR) motif and a P-loop sequence; recombinant protein binds GTP (blot overlay assay with [α-32P]GTP), possesses GTPase activity, and is phosphorylated in vitro by PKC. The protein localizes to the postacrosomal zone surface of human spermatozoa and to germ cells (particularly large pachytene primary spermatocytes) in the seminiferous epithelium. Recombinant protein expression in E. coli, GTP-binding blot overlay assay, GTPase activity assay, PKC phosphorylation in vitro, immunostaining of human testis and spermatozoa Molecular human reproduction Medium 11517287
2006 The HSD-0.7 fragment of HSD-3.8 (SPATA7) interacts with the C-terminal 144 amino acids of G-protein beta1 subunit (Gβ1) in a GDP-dependent manner; co-transfection in HEK293 cells shows colocalization in cytoplasm and complex formation. Overexpression of HSD-0.7 activates ERK1/2 via a PKC-dependent (not Ras-dependent) pathway; truncated fragments lacking either the TPR domain or P-loop fail to activate ERK1/2. Yeast two-hybrid screen, co-transfection with HA/FLAG-tagged constructs in HEK293 cells, co-immunoprecipitation, immunofluorescence colocalization, ERK1/2 activation assay with domain-deletion mutants Frontiers in bioscience Medium 16368546
2025 In Standard poodle dogs with a large deletion removing the 3' end of SPATA7 (predicted to truncate protein from 595 to 361 AA), ultrastructure expansion microscopy (U-ExM) detects SPATA7 signal around the transition zone of the primary cilium in photoreceptors and fibroblasts of wild-type dogs, which is absent in affected dogs. Ptpn21 knockout mice show no ocular phenotype, implicating SPATA7 (not PTPN21) as the causal gene for the cone-rod dystrophy phenotype. GWAS, homozygosity mapping, ultrastructure expansion microscopy (U-ExM), Ptpn21 knockout mouse phenotyping, retinal RNA/IHC analysis PLoS genetics Medium 41325489
2002 The 0.7 kb fragment of HSD-3.8 (SPATA7/HSD-0.7) interacts with the C-terminal 144 amino acids of human G-protein beta1 subunit in yeast two-hybrid assay; truncated bait plasmids lacking portions of HSD-0.7 lose the ability to interact, indicating the interaction requires the integrity of the bait protein. Yeast two-hybrid screening of human ovary cDNA library with HSD-0.7 bait, truncation analysis Acta Academiae Medicinae Sinicae Low 12905684

Source papers

Stage 0 corpus · 34 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 Mutations in SPATA7 cause Leber congenital amaurosis and juvenile retinitis pigmentosa. American journal of human genetics 96 19268277
2014 Spata7 is a retinal ciliopathy gene critical for correct RPGRIP1 localization and protein trafficking in the retina. Human molecular genetics 52 25398945
2018 SPATA7 maintains a novel photoreceptor-specific zone in the distal connecting cilium. The Journal of cell biology 43 29899041
2011 Screening of SPATA7 in patients with Leber congenital amaurosis and severe childhood-onset retinal dystrophy reveals disease-causing mutations. Investigative ophthalmology & visual science 33 21310915
2012 Clinical and molecular spectrum of patients with 17β-hydroxysteroid dehydrogenase type 3 (17-β-HSD3) deficiency. Arquivos brasileiros de endocrinologia e metabologia 27 23295294
2015 AAV8(Y733F)-mediated gene therapy in a Spata7 knockout mouse model of Leber congenital amaurosis and retinitis pigmentosa. Gene therapy 21 25965394
2010 Spectrum of SPATA7 mutations in Leber congenital amaurosis and delineation of the associated phenotype. Human mutation 21 20104588
2005 Identification of novel functional inhibitors of 17beta-hydroxysteroid dehydrogenase type III (17beta-HSD3). The Prostate 21 15924334
2001 Expression and function of the HSD-3.8 gene encoding a testis-specific protein. Molecular human reproduction 15 11517287
2014 Human 3-alpha hydroxysteroid dehydrogenase type 3 (3α-HSD3): the V54L mutation restricting the steroid alternative binding and enhancing the 20α-HSD activity. The Journal of steroid biochemistry and molecular biology 13 24434280
2006 A sperm component, HSD-3.8 (SPAG1), interacts with G-protein beta 1 subunit and activates extracellular signal-regulated kinases (ERK). Frontiers in bioscience : a journal and virtual library 13 16368546
2016 SPATA7: Evolving phenotype from cone-rod dystrophy to retinitis pigmentosa. Ophthalmic genetics 12 26854980
2017 Conditional loss of Spata7 in photoreceptors causes progressive retinal degeneration in mice. Experimental eye research 11 29100828
2006 Synthesis, biochemical evaluation and rationalisation of the inhibitory activity of a series of 4-hydroxyphenyl ketones as potential inhibitors of 17beta-hydroxysteroid dehydrogenase type 3 (17beta-HSD3). Bioorganic & medicinal chemistry letters 9 16797984
2019 Spectrum, frequency, and genotype-phenotype of mutations in SPATA7. Molecular vision 8 31908400
2017 QSAR Study of 17β-HSD3 Inhibitors by Genetic Algorithm-Support Vector Machine as a Target Receptor for the Treatment of Prostate Cancer. Iranian journal of pharmaceutical research : IJPR 8 29201087
2022 Spata7 is required for maintenance of the retinal connecting cilium. Scientific reports 7 35368022
2015 Novel homozygous large deletion including the 5' part of the SPATA7 gene in a consanguineous Israeli Muslim Arab family. Molecular vision 6 25814828
2021 16-Picolyl-androsterone derivative exhibits potent 17β-HSD3 inhibitory activity, improved metabolic stability and cytotoxic effect on various cancer cells: Synthesis, homology modeling and docking studies. The Journal of steroid biochemistry and molecular biology 5 33609690
2020 The spermatogenesis-associated protein-7 (SPATA7) gene - an overview. Ophthalmic genetics 5 32799588
2011 Lack of phenotypic effect of triallelic variation in SPATA7 in a family with Leber congenital amaurosis resulting from CRB1 mutations. Molecular vision 5 22219627
2008 Synthesis, biochemical evaluation and rationalisation of the inhibitory activity of a range of 4-hydroxyphenyl ketones as potent and specific inhibitors of the type 3 of 17beta-hydroxysteroid dehydrogenase (17beta-HSD3). The Journal of steroid biochemistry and molecular biology 5 18620056
2022 Chemical synthesis of fluorinated and iodinated 17β-HSD3 inhibitors and evaluation for imaging prostate cancer tumors and tissue biodistribution. Bioorganic chemistry 3 36174444
2019 Rare compound heterozygous missense SPATA7 variations and risk of schizophrenia; whole-exome sequencing in a consanguineous family with affected siblings, follow-up sequencing and a case-control study. Neuropsychiatric disease and treatment 3 31695380
2025 17β-hydroxysteroid dehydrogenase type 3 (17β-HSD3) deficiency patient with gender dysphoria: insights into challenges in management. BMJ case reports 1 40615130
2025 Two genes, one culprit - a functional candidate validation of a SPATA7 deletion in dogs with day blindness/retinal degeneration. PLoS genetics 1 41325489
2022 Lessons from 17β-HSD3 deficiency: Clinical spectrum and complex molecular basis in Chinese patients. The Journal of steroid biochemistry and molecular biology 1 36154887
2019 Targeted sequencing of linkage region in Dominican families implicates PRIMA1 and the SPATA7-PTPN21-ZC3H14-EML5-TTC8 locus in carotid-intima media thickness and atherosclerotic events. Scientific reports 1 31406157
2015 [Effect of electroacupuncture intervention on expression of testicular P 450 scc/17 β-HSD3 in rats with partial androgen deficiency]. Zhen ci yan jiu = Acupuncture research 1 25845214
2002 [Study on the function of HSD-3.8 gene encoding a testis-specific protein with yeast two-hybrid system]. Zhongguo yi xue ke xue yuan xue bao. Acta Academiae Medicinae Sinicae 1 12905684
2026 Computational identification of Terminalia arjuna phytochemicals as potential 3α-HSD3 inhibitors. Scientific reports 0 41775750
2025 Identifying 17-β-HSD3 Deficiency in Patients with Karyotype 46,XY Misdiagnosed with Androgen Insensitivity Syndrome: A Pediatric Case Report. The American journal of case reports 0 41035179
2025 Unmasking a rare variant: 17β-HSD3 deficiency in a male infant with disorders of sex development. BMJ case reports 0 41397774
2009 Down-regulation of murine testicular 17β-HSD3 and hepatic CYP1A2 enzymes by a bovine testes extract. Reproductive medicine and biology 0 29699329

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