Affinage

AHI1

Jouberin · UniProt Q8N157

Length
1196 aa
Mass
137.1 kDa
Annotated
2026-06-09
78 papers in source corpus 31 papers cited in narrative 31 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/6 claims corpus-supported (83%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

AHI1 (Jouberin) is a modular SH3- and WD40-repeat scaffolding/adaptor protein that operates at the primary cilium transition zone and in neuronal cytoplasmic signaling, with loss-of-function mutations causing Joubert syndrome featuring cerebellar malformation and abnormal axonal decussation (PMID:15322546, PMID:15467982). At the ciliary base, AHI1 localizes to the mother centriole/basal body, where its recruitment to a ring-shaped transition-zone domain depends on Cby1, and where it is required for ciliogenesis and polarized vesicular trafficking by stabilizing the small GTPase Rab8a (PMID:19625297, PMID:25103236). AHI1 governs ciliary cargo: it sustains Arl13b ciliary membrane localization and proteasomal stability to support Sonic hedgehog signaling and proper axoneme length, mediates outer-segment protein transport in photoreceptors, and targets the GPCRs MCHR1 to the ciliary membrane for downstream cAMP/ERK signaling (PMID:20592197, PMID:31391239, PMID:33741721). Its WD40 region binds NPHP1, and Joubert/retinitis pigmentosa mutations in this region destabilize AHI1 and impair its ciliary-base enrichment, whereas the C-terminal SH3 domain is dispensable for normal development (PMID:23532844, PMID:25616960, PMID:28442542). In neurons AHI1 forms a stable complex with HAP1 that regulates TrkB receptor endocytic sorting and signaling, and AHI1 controls additional partners including 5-HT2CR, Cend1, GR, and APP to influence neurite outgrowth, feeding behavior, and stress-related/depressive phenotypes (PMID:18636121, PMID:20956301, PMID:22123816, PMID:23658157, PMID:31062249, PMID:33782379). Beyond ciliary and neuronal roles, AHI1 has hematopoietic and immune functions: an AHI-1/BCR-ABL/JAK2 complex assembled via its SH3 domain modulates JAK2-STAT5 phosphorylation and tyrosine kinase inhibitor resistance in leukemia, and AHI1 recruits the deubiquitinase OTUD1 to stabilize Tyk2 and maintain basal type-I interferon signaling (PMID:18936234, PMID:22623184, PMID:35821088).

Mechanistic history

Synthesis pass · year-by-year structured walk · 26 steps
  1. 2002 Medium

    Established AHI1's molecular architecture and first link to signal transduction by identifying it as a provirus-targeted gene encoding an SH3/WD40 modular protein.

    Evidence cDNA cloning and provirus integration mapping in Abelson pre-B-cell lymphomas

    PMID:12186888

    Open questions at the time
    • No direct binding partners or substrates defined
    • Functional consequence of truncation not yet shown
  2. 2004 High

    Defined AHI1 as the causative gene for Joubert syndrome, connecting its loss to cerebellar malformation and abnormal axonal decussation and anchoring its developmental role.

    Evidence Human mutation identification with brain expression analysis

    PMID:15322546 PMID:15467982

    Open questions at the time
    • Molecular mechanism of axon guidance defect unresolved
    • Cellular pathway connecting mutations to phenotype not yet defined
  3. 2008 High

    Placed AHI1 at the ciliary basal body and established its requirement for ciliogenesis via Rab8a stabilization and polarized vesicle trafficking.

    Evidence shRNAi knockdown, knockout mouse, immunolocalization and trafficking assays

    PMID:19625297

    Open questions at the time
    • Direct biochemical interaction with Rab8a not demonstrated
    • How AHI1 stabilizes Rab8a mechanistically unknown
  4. 2008 High

    Identified a stable AHI1-HAP1 complex that regulates TrkB receptor internalization and signaling, linking AHI1 to neuronal differentiation distinct from its ciliary role.

    Evidence Reciprocal Co-IP, HAP1-KO mouse, neurite outgrowth and TrkB signaling assays

    PMID:18636121

    Open questions at the time
    • Binding interface within AHI1 not mapped
    • Relationship between HAP1 complex and ciliary function unclear
  5. 2008 High

    Revealed an oncogenic role through an AHI-1/BCR-ABL/JAK2 complex modulating JAK2-STAT5 phosphorylation and TKI resistance in leukemia.

    Evidence Co-IP, RNAi/overexpression in hematopoietic cells, in vivo leukemia induction, phosphorylation assays

    PMID:18936234

    Open questions at the time
    • Which AHI1 domain mediates complex assembly not yet resolved here
    • Whether interactions are direct unconfirmed
  6. 2009 Medium

    Extended AHI-1 signaling in lymphoma by linking it to HCK kinase and BIN1 effectors and autocrine cytokine production.

    Evidence Retroviral RNAi, microarray, Western blot and single Co-IP (BIN1-MYC) in CTCL cells

    PMID:19211505

    Open questions at the time
    • BIN1-MYC interaction rests on a single Co-IP
    • Direct vs indirect link of AHI-1 to HCK not established
  7. 2010 High

    Demonstrated cilium-specific cargo trafficking by showing AHI1 is needed for photoreceptor outer segment formation and selective outer-segment protein transport, again via Rab8a.

    Evidence KO mouse histology, opsin/transducin/Rom1 localization, Nphp1 genetic epistasis and opsin dosage rescue

    PMID:20081859 PMID:20592197

    Open questions at the time
    • Direct AHI1-Rab8a biochemistry still inferred
    • Selectivity mechanism for ciliary versus synaptic cargo unknown
  8. 2010 High

    Connected neuronal AHI1 loss to TrkB degradation and depressive phenotypes, establishing a behaviorally relevant TrkB-signaling axis.

    Evidence Conditional Cre-loxP KO, endocytic TrkB degradation assay, viral TrkB rescue in amygdala

    PMID:20956301

    Open questions at the time
    • Whether TrkB regulation requires HAP1 complex not addressed
    • Mechanism of endocytic sorting unresolved
  9. 2011 Medium

    Generalized the ciliary requirement across systems and added a cell-cell junction role using zebrafish and renal epithelial loss-of-function.

    Evidence Zebrafish morpholino, siRNA in renal cells, cilia and junction assessment

    PMID:21959375

    Open questions at the time
    • Junction-formation mechanism undefined
    • Morpholino specificity concerns inherent to method
  10. 2011 Medium

    Identified AHI1 as a regulator of 5-HT2CR lysosomal degradation in the hypothalamus, linking it to feeding behavior and body weight.

    Evidence Co-IP, co-localization, lysosomal inhibitor assays, hypothalamic knockdown, feeding measurement

    PMID:22123816

    Open questions at the time
    • Direct binding site not mapped
    • Single-lab finding without reciprocal validation
  11. 2012 High

    Resolved the AHI-1 SH3 domain crystal structure and showed its deletion sensitizes BCR-ABL+ cells to TKIs, identifying Dynamin-2 as an SH3 partner.

    Evidence X-ray crystallography (1.53 Å), SH3 deletion mutagenesis, Co-IP, apoptosis assay

    PMID:22623184

    Open questions at the time
    • Functional role of Dynamin-2 interaction not explored
    • Structure of WD40 region unresolved
  12. 2013 High

    Mapped binding determinants and partners (NGF-regulated HAP1A, Cend1) and clarified that JBTS mutations destabilize AHI1 and disrupt NPHP1 binding while HAP1 binding is dispensable for ciliogenesis.

    Evidence Co-IP, mass spectrometry, mutant constructs, protein stability and ciliogenesis assays in patient fibroblasts, Cend1 rescue

    PMID:23532844 PMID:23658157

    Open questions at the time
    • How NPHP1 binding supports ciliary localization mechanistically unknown
    • Structural basis of mutation effects on WD40 fold not solved
  13. 2014 High

    Identified Cby1 as the upstream factor recruiting AHI1 to a defined transition-zone ring at the centriole-cilium interface.

    Evidence Superresolution microscopy (3D-SIM, STED) and Cby1-KO cells

    PMID:25103236

    Open questions at the time
    • Direct Cby1-AHI1 interaction not biochemically confirmed
    • Functional consequence of mislocalized AHI1 in Cby1-KO not measured
  14. 2015 High

    Distinguished functional from dispensable domains, showing C-terminal SH3 truncations are non-pathogenic and pathogenicity requires N-terminal WD40 disruption.

    Evidence Whole-exome sequencing, homozygosity mapping, zebrafish morpholino N- vs C-terminal targeting

    PMID:25616960

    Open questions at the time
    • Precise WD40 functional motifs not delineated
    • Reconciliation with SH3's role in leukemia not addressed
  15. 2017 Medium

    Linked WD40-domain missense variants to non-syndromic retinitis pigmentosa via reduced ciliary-base enrichment of Jouberin.

    Evidence Exome sequencing, homology modeling, recombinant mutant expression in ciliated RPE cells

    PMID:28442542

    Open questions at the time
    • Mechanism of base enrichment loss undefined
    • Single-lab functional assay
  16. 2017 Medium

    Refined the photoreceptor phenotype, showing Ahi1 is required for outer-segment disc morphogenesis and maintenance but not basic connecting cilium formation.

    Evidence TALEN zebrafish mutant, histology, EM, transition-zone protein localization

    PMID:28118669

    Open questions at the time
    • Molecular cargo defect underlying disc phenotype unresolved
    • Species-specific differences not reconciled
  17. 2019 High

    Established AHI1's control of Arl13b ciliary localization/stability and downstream Shh signaling, axoneme length, and PDGFR-α-dependent cell migration.

    Evidence Ahi1-KO MEFs with Ahi1-GFP rescue, proteasome inhibition, Smo/Gli and migration assays

    PMID:31391239

    Open questions at the time
    • Whether AHI1 directly binds Arl13b not shown
    • Link between Arl13b stabilization and Rab8a pathway unclear
  18. 2019 High

    Resolved a long-standing question by showing the retinal axon misprojection phenotype reflects a toxic gain-of-function of truncated Ahi1 rather than loss of function.

    Evidence Zebrafish morpholino/CRISPR truncation versus null comparison, RGC axon analysis

    PMID:30949029

    Open questions at the time
    • Molecular basis of toxic gain-of-function undefined
    • Relevance to human Joubert axon phenotype not directly tested
  19. 2019 Medium

    Identified an APP-binding role for AHI1 that inhibits amyloidogenic processing and enhances ERK-dependent survival, linking AHI1 to Alzheimer-relevant biology.

    Evidence Co-IP, Western blot for CTFβ/Aβ42, overexpression and knockdown in AD model cells

    PMID:31062249

    Open questions at the time
    • Direct vs indirect AHI1-APP interaction not resolved
    • In vivo relevance to disease progression untested
  20. 2021 High

    Expanded AHI1's GPCR-trafficking role to ciliary targeting of MCHR1, demonstrating ciliary localization is required for downstream cAMP/ERK signaling.

    Evidence Ahi1-/- neuronal culture, ciliary vs surface MCHR1 immunofluorescence, cAMP and ERK assays

    PMID:33741721

    Open questions at the time
    • Mechanism of selective ciliary targeting unknown
    • Whether AHI1 directly binds MCHR1 not established
  21. 2021 Medium

    Defined AHI1 as a cytoplasmic stabilizer and translocation regulator of the glucocorticoid receptor under stress, with behavioral antidepressant consequences.

    Evidence Co-IP, Ahi1-KO mouse, nuclear/cytoplasmic fractionation, antidepressant treatment

    PMID:33782379

    Open questions at the time
    • Direct binding interface not mapped
    • Single-lab finding
  22. 2021 Medium

    Identified Tet2 as an AHI1 partner whose stress-induced nuclear translocation depends on AHI1, linking AHI1 to epigenetic regulation.

    Evidence Tet2 IP mass spectrometry, Co-IP, Ahi1-KO/knockdown, fractionation, 5hmC profiling

    PMID:34218273

    Open questions at the time
    • Functional outcome of altered Tet2 localization on gene expression incompletely defined
    • Single-lab finding
  23. 2022 High

    Established AHI1 as a stabilizer of basal type-I interferon signaling by recruiting OTUD1 to deubiquitinate and stabilize Tyk2, connecting it to antiviral immunity.

    Evidence Co-IP of AHI1-OTUD1-Tyk2 complex, ubiquitination assays, knockdown/KO, patient PBMCs and depression model mice

    PMID:35821088

    Open questions at the time
    • Domain of AHI1 mediating OTUD1/Tyk2 recruitment not mapped
    • Relationship to other JAK-family roles unexplored
  24. 2022 Medium

    Extended the GR axis to serotonin synthesis via GR/ERβ/TPH2 regulation and explained sex differences in depressive behavior through E2 levels.

    Evidence Dual-luciferase reporter of GR-ERβ promoter binding, knockdown, Ahi1-KO mouse, ERβ agonist rescue, E2 measurement

    PMID:35643536

    Open questions at the time
    • Mechanism of sex-specific E2 effect undefined
    • Single-lab finding
  25. 2023 Medium

    Revealed a mitochondrial AHI1/GR complex that, with TFAM, regulates mtDNA copy number and brain ATP via D-loop binding, linking AHI1 to bioenergetics and exercise responses.

    Evidence Co-IP, ChIP-qPCR of GR binding to mtDNA D-loop, mitochondrial fractionation, Ahi1-KO mouse, mtDNA/ATP assays

    PMID:36691038

    Open questions at the time
    • How AHI1 reaches mitochondria not defined
    • Single-lab finding
  26. 2025 Low

    Showed CEP290 is required for proper spatial distribution of AHI1 within the connecting cilium, placing AHI1 downstream of CEP290 in transition-zone organization.

    Evidence CEP290-null mouse retina with super-resolution immunostaining (preprint)

    PMID:bio_10.1101_2025.01.20.633784

    Open questions at the time
    • Preprint, single observational study without functional rescue
    • AHI1-CEP290 biochemical relationship not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single scaffold reconciles its transition-zone ciliary cargo functions with its diverse cytoplasmic, mitochondrial, immune, and oncogenic partner interactions remains unresolved.
  • No unified domain-mapping across AHI1's many partners
  • Whether ciliary and non-ciliary roles share a common biochemical activity is unknown
  • No high-resolution structure of the WD40 region

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 4 GO:0098772 molecular function regulator activity 4
Localization
GO:0005815 microtubule organizing center 3 GO:0005829 cytosol 3 GO:0005929 cilium 3 GO:0005634 nucleus 2 GO:0005739 mitochondrion 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-9609507 Protein localization 4 R-HSA-1266738 Developmental Biology 3 R-HSA-392499 Metabolism of proteins 2 R-HSA-168256 Immune System 1
Partners
ARL13BBCR-ABLGRHAP1JAK2NPHP1OTUD1RAB8A
Complex memberships
AHI-1/BCR-ABL/JAK2 complexAHI1-HAP1 complexAHI1-OTUD1-Tyk2 complex

Evidence

Reading pass · 31 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 AHI1 encodes a modular protein containing one SH3 domain and seven WD40 repeats, and was identified as a gene targeted by provirus insertional mutations in Abelson pre-B-cell lymphomas. Proviral insertions at the 3' end of the gene produced truncated Ahi-1/viral fused transcripts, including splicing variants with deletion of the SH3 domain, implicating it in signal transduction. cDNA cloning, Northern blot, provirus integration site mapping, transcript analysis Journal of virology Medium 12186888
2004 AHI1 is most highly expressed in neurons that give rise to the crossing axons of the corticospinal tract and superior cerebellar peduncles, and loss-of-function mutations cause Joubert syndrome with abnormal axonal decussation and cerebellar malformation. Human genetics (mutation identification), in situ hybridization/expression analysis Nature genetics High 15322546
2004 AHI1 (encoding Jouberin) contains WD40 repeats, an SH3 domain, and numerous SH3-binding sites, and is expressed strongly in embryonic hindbrain and forebrain, indicating roles in cerebellar and cortical development. Frameshift and missense mutations cause Joubert syndrome with cortical polymicrogyria. Mutation identification by sequencing, expression analysis American journal of human genetics Medium 15467982
2008 Ahi1 protein localizes to the mother centriole (basal body of the primary cilium). Knockdown of Ahi1 by shRNAi or targeted Ahi1 deletion impairs ciliogenesis. In Ahi1-knockdown cells, Rab8a (a small GTPase critical for polarized membrane trafficking) is destabilized and fails to localize properly to the basal body, causing defects in endocytic vesicle trafficking from the plasma membrane to the Golgi and back. shRNAi knockdown, Ahi1 knockout mouse, immunofluorescence/localization, vesicle trafficking assays, ciliogenesis assays Human molecular genetics High 19625297
2008 Mouse Ahi1 forms a stable protein complex with huntingtin-associated protein 1 (Hap1). Hap1-knockout mice show significantly reduced Ahi1 levels, defective cerebellar development, and abnormal axonal decussation. Suppression of Ahi1 also decreases Hap1 levels. Truncated Ahi1 (corresponding to Joubert syndrome mutations) inhibits neurite outgrowth in neuronal culture. The Ahi1-Hap1 complex regulates TrkB receptor internalization and signaling (reducing TrkB-mediated neurogenesis/differentiation). Co-immunoprecipitation, Hap1-KO mouse analysis, Ahi1 suppression, neurite outgrowth assay, TrkB signaling measurement The Journal of clinical investigation High 18636121
2008 Murine Ahi1 is distributed throughout the cytoplasm, dendrites, and axons of neurons but is absent from glial cells. Ahi1 protein consistently accumulates in the stigmoid body, a cytoplasmic organelle found in neurons. Immunohistochemistry, comparative expression analysis (human, mouse, zebrafish), subcellular localization The Journal of comparative neurology Medium 18785627
2008 AHI-1 overexpression in murine and human hematopoietic cells confers growth advantages in vitro and induces leukemia in vivo, enhancing BCR-ABL effects. AHI-1, BCR-ABL, and JAK2 form a physical interaction complex. Modulation of AHI-1 expression regulates phosphorylation of BCR-ABL and JAK2-STAT5. RNAi-mediated suppression of AHI-1 in CML stem/progenitor cells reduces growth autonomy. This complex mediates tyrosine kinase inhibitor (TKI) resistance. Co-immunoprecipitation (AHI-1-BCR-ABL-JAK2 complex), RNAi knockdown, overexpression in hematopoietic cells, in vivo leukemia induction, phosphorylation assays The Journal of experimental medicine High 18936234
2009 Knockdown of AHI-1 in CTCL cells identifies HCK (tyrosine kinase) and BIN1 (tumor suppressor) as downstream effectors. Changes in HCK phosphorylation were observed upon AHI-1 suppression or overexpression. BIN1 physically interacts with MYC in CTCL cells. AHI-1 suppression alters autocrine cytokine production (IL-2, IL-4, TNFα). Retroviral RNAi knockdown, microarray, qRT-PCR, Western blot, co-immunoprecipitation (BIN1-MYC) Blood Medium 19211505
2010 Ahi1-null mice fail to form retinal photoreceptor outer segments and have abnormal distribution of opsin throughout photoreceptors. Photoreceptor apoptosis occurs rapidly between 2-4 weeks of age. This phenotype shows dosage-sensitive genetic interaction with Nphp1 (another ciliopathy gene), and reducing opsin dosage significantly delays cell death. Ahi1 knockout mouse, histology, immunostaining, opsin localization, genetic epistasis (Ahi1/Nphp1 double mutant) Nature genetics High 20081859
2010 In Ahi1-/- mice, photoreceptor outer segment proteins (transducin, Rom1) fail to be transported appropriately or are significantly reduced, while synaptic proteins are correctly trafficked. Vesicular targeting defects are cilium-specific. Rab8a expression is decreased in Ahi1-/- mice, suggesting Ahi1 stabilizes Rab8a to mediate polarized vesicular trafficking to the outer segment. Ahi1 knockout mouse, immunostaining for synaptic vs. outer segment proteins, electron microscopy, Rab8a expression analysis The Journal of neuroscience High 20592197
2010 Neuronal-specific Ahi1 deficiency (Cre-loxP) reduces TrkB levels in the brain and causes depressive phenotypes. Ahi1 deficiency promotes degradation of endocytic TrkB and reduces TrkB signaling in neuronal cells. Overexpression of TrkB in the amygdala rescues depressive phenotypes. Conditional Cre-loxP KO, TrkB level and signaling measurement, endocytic TrkB degradation assay, viral TrkB overexpression rescue Proceedings of the National Academy of Sciences of the United States of America High 20956301
2011 In zebrafish ahi1 morphants, knockdown causes loss of cilia at Kupffer's vesicle and subsequently defects in cardiac left-right asymmetry. siRNA knockdown in renal epithelial cells demonstrates a role for Ahi1 in both ciliogenesis and cell-cell junction formation. Zebrafish morpholino knockdown, whole-mount immunostaining, siRNA in renal epithelial cells, cilia assessment Cellular and molecular life sciences : CMLS Medium 21959375
2011 Hypothalamic Ahi1 interacts with serotonin receptor 2C (5-HT2CR) and promotes its degradation via the lysosomal pathway. Knockdown of hypothalamic Ahi1 increases 5-HT2CR expression and decreases food intake and body weight. Ahi1 regulates neuropeptide Y and POMC expression downstream of this interaction. Co-immunoprecipitation, co-localization, lysosomal inhibitor assays, Ahi1 knockdown (hypothalamic injection), feeding behavior measurement The Journal of biological chemistry Medium 22123816
2012 Crystal structure of the AHI-1 SH3 domain resolved at 1.53-Å resolution reveals canonical SH3 folding with an unusual C-terminal α-helix. Deletion of the SH3 domain significantly enhances apoptotic response of BCR-ABL+ cells to TKIs. A novel interaction between AHI-1 and Dynamin-2 (a GTPase) was identified through the SH3 domain. PD1R peptide modeling suggests an 'Arg-Arg-Trp' stack forms within the binding interface. X-ray crystallography (1.53 Å), SH3 domain deletion mutagenesis, co-immunoprecipitation (AHI-1/Dynamin-2), apoptosis assay Proteomics High 22623184
2013 Full-length (but not N-terminal) Ahi1 binds Hap1, and this interaction is regulated by nerve growth factor: NGF induces dephosphorylation of Hap1A and decreases its association with Ahi1. Ahi1 associates with phosphorylated Hap1A in cytosolic but not synaptosomal fractions. Mass spectrometry of cytosolic Ahi1 immunoprecipitates identifies Cend1 (BM88) as a binding partner. Loss of Ahi1 reduces Cend1 levels in the hypothalamus; overexpressed Ahi1 stabilizes Cend1; and Cend1 overexpression rescues neurite extension defects in Ahi1-KO hypothalamic neurons. Co-immunoprecipitation, mass spectrometry, Western blot (subcellular fractionation), NGF treatment, Ahi1-KO mouse, rescue by Cend1 overexpression The Journal of neuroscience High 23658157
2013 The Joubert syndrome-associated AHI1 missense mutation V443D (in a region with no known protein motifs) reduces AHI1 stability by 50%, causes aberrant localization of AHI1 at basal bodies and cell-cell junctions, and decreases AHI1 binding to NPHP1. Another JBTS-causing mutation, R351L, shows similar mislocalization. Primary cilia formation is decreased in fibroblasts from individuals with JBTS and AHI1 mutations. HAP1 has decreased binding to AHI1-V443D, but Hap1-deficient fibroblasts and neurons form primary cilia normally, indicating Hap1-Ahi1 binding is not critical for ciliary function. Transfection of mutant constructs, immunofluorescence localization, Co-immunoprecipitation (AHI1-NPHP1, AHI1-HAP1), protein stability assays, ciliogenesis assay in patient fibroblasts, Hap1-KO analysis The Journal of biological chemistry High 23532844
2014 Cby1 promotes Ahi1 recruitment to a ring-shaped domain (~250 nm) at the distal end of mature centrioles (centriole-cilium interface), as revealed by superresolution microscopy (3D-SIM and STED). The amount of centriole-localized Ahi1 (but not Ofd1) is reduced in Cby1-/- cells, indicating Cby1 is required for efficient recruitment of Ahi1 to the transition zone. Superresolution microscopy (3D-SIM, STED), Cby1 knockout mouse cells, immunostaining Molecular biology of the cell High 25103236
2015 C-terminal truncations of AHI1 (p.Arg1066* and p.Trp1088Leufs*16) are non-pathogenic when homozygous in humans — carriers do not manifest Joubert syndrome. Morpholinos against N-terminal zebrafish Ahi1 (orthologous to where human mutations cluster) produced ciliopathy phenotype, but targeting near the human C-terminal truncation sites did not, establishing that the C-terminal SH3 domain is dispensable for normal development and that pathogenicity requires disruption of N-terminal WD40-repeat-containing regions. Whole-exome sequencing, homozygosity mapping, zebrafish morpholino (N-terminal vs. C-terminal targeting), clinical phenotyping Human molecular genetics High 25616960
2017 AHI1 missense variants in the WD40 domain cause non-syndromic retinitis pigmentosa. Expression of mutant recombinant Jouberin in ciliated RPE cells shows significantly decreased enrichment at the ciliary base, without changes in overall ciliation percentage, cilium length, or IFT. 3D structure homology modeling predicts structural implications of WD40-domain missense variants. Exome sequencing, 3D homology modeling, patient fibroblast ciliogenesis assay, recombinant protein expression in ciliated RPE cells, immunofluorescence localization Journal of medical genetics Medium 28442542
2017 Zebrafish ahi1lri46 (TALEN-generated) mutants develop shorter cone outer segments but normal rod morphology at 5 dpf; by 5 months, cone degeneration and rhodopsin mislocalization in rods occurs. The connecting cilium forms normally and Cc2d2a and Cep290 localize properly, indicating Ahi1 is required for disc morphogenesis and outer segment maintenance but not for basic connecting cilium formation. TALEN-generated zebrafish mutant, histology, electron microscopy, immunohistochemistry, optokinetic response assay Investigative ophthalmology & visual science Medium 28118669
2018 AHI1 loss in Ahi1-KO mice downregulates tyrosine hydroxylase (TH) in the midbrain. Rev-Erbα (a TH transcriptional repressor) and BMAL1 (Rev-Erbα transcriptional regulator) are upregulated in Ahi1-KO midbrains. AHI1 decreases BMAL1/Rev-Erbα expression by interacting with and repressing RORα (a nuclear receptor and circadian gene transcriptional regulator). Bmal1 deficiency reverses TH reduction caused by Ahi1 deficiency. Rev-Erbα inhibitor microinfusion into ventral midbrain of Ahi1-KO mice increases TH and improves depressive symptoms. Ahi1-KO mouse, Western blot, Ahi1-knockdown cells, co-immunoprecipitation (AHI1-RORα), genetic epistasis (Ahi1 KO x Bmal1 KO), pharmacological rescue (SR8278) The Journal of biological chemistry Medium 29449373
2019 Deletion of Ahi1 in mouse embryonic fibroblasts (MEFs) reduces localization of Arl13b to the ciliary membrane (without changing total or membrane-associated Arl13b levels), decreases non-membrane-associated Arl13b stability via the proteasome pathway, decreases sonic hedgehog signaling, and causes abnormally elongated ciliary axoneme with increased ciliary IFT88. Ahi1-/- MEFs display defects in cell motility and Pdgfr-α-dependent migration. Exogenous Ahi1-GFP restores ciliary length, Arl13b ciliary recruitment, and Arl13b stability. Ahi1 KO MEFs, immunofluorescence, Smo/Gli signaling assay, proteasome inhibitor assay, exogenous rescue (Ahi1-GFP), cell migration/motility assay Journal of cell science High 31391239
2019 AHI1 physically interacts with APP (amyloid precursor protein) in mouse brain and transfected cells. AHI1 expression facilitates intracellular translocation of APP and inhibits APP amyloidogenic processing, reducing APP-CTFβ and secreted Aβ42. AHI1 is reduced in AD model cells (expressing Swedish/Indiana APP) and in 3xTg-AD mouse brain. AHI1-APP interaction enhances Erk activation and restores cell survival and differentiation. Co-immunoprecipitation (AHI1-APP), Western blot (CTFβ, Aβ42), AHI1 overexpression in AD model cells, Ahi1-KD cells, Erk signaling assay Molecular neurobiology Medium 31062249
2019 Mutant Ahi1 lacking intact WD40 repeats (generated by morpholino or CRISPR/Cas9 truncation in zebrafish) causes retinal ganglion cell axon misprojection and ocular dysplasia, whereas ahi1 null zebrafish show normal RGC axon projection and ocular morphology, demonstrating that the aberrant retinal axon projection phenotype is caused by a toxic gain-of-function of truncated Ahi1 rather than loss of Ahi1. Zebrafish morpholino (generating truncated Ahi1), CRISPR/Cas9 truncation, ahi1 null zebrafish comparison, in situ hybridization, RGC axon projection analysis Frontiers in cellular neuroscience High 30949029
2021 Ahi1 regulates the nuclear translocation of glucocorticoid receptor (GR): stress-mediated GR nuclear translocation reduces Ahi1 in stressed cells and mouse brains. Ahi1 interacts with GR to stabilize each other in the cytoplasm. Ahi1 deficiency promotes GR degradation in the cytoplasm and reduces GR nuclear translocation in response to stress. Ahi1-KO mice show hyposensitivity to antidepressants under stress. Co-immunoprecipitation (Ahi1-GR), Western blot, Ahi1-KO mouse, nuclear/cytoplasmic fractionation, antidepressant treatment Translational psychiatry Medium 33782379
2021 AHI1 regulates neuronal ciliary trafficking of melanin-concentrating hormone receptor 1 (MCHR1): loss of Ahi1 in mouse neurons significantly reduces MCHR1 in the ciliary membrane without affecting total or surface MCHR1 expression. Ahi1-/- neurons show decreased cAMP and ERK signaling upon MCH stimulation, demonstrating that ciliary localization of MCHR1 is necessary for its downstream signaling. Ahi1-/- neuronal culture, immunofluorescence (ciliary vs. total MchR1), cAMP assay, ERK phosphorylation assay, MCH stimulation The Journal of neuroscience High 33741721
2021 Chronic stress induces abnormal nuclear translocation of Tet2. Ahi1 physically interacts with Tet2 (identified by Tet2 immunoprecipitation and mass spectrometry). Ahi1 knockout or knockdown causes accumulation of Tet2 in the cytosol. Reduction of Ahi1 protein under chronic stress explains Ahi1-dependent Tet2 nuclear translocation defects. Co-immunoprecipitation, mass spectrometry (Tet2 IP), Ahi1-KO mouse, siRNA knockdown, nuclear/cytoplasmic fractionation, 5hmC profiling Human molecular genetics Medium 34218273
2022 AHI1 acts as a critical stabilizer of basal type-I interferon (IFN-I) signaling. Mechanistically, AHI1 recruits OTUD1 (a deubiquitinase) to deubiquitinate and stabilize Tyk2. AHI1 reduction (induced by depression-related AVP/arginine vasopressin) downregulates Tyk2 and IFN-I signaling activity in macrophages. AVP reduces AHI1 in macrophages, leading to attenuated antiviral immune response. Co-immunoprecipitation (AHI1-OTUD1-Tyk2 complex), ubiquitination assays, AHI1 knockdown/KO, IFN-I signaling measurement, patient PBMCs, depression model mice Cell research High 35821088
2022 Ahi1 regulates serotonin production via the GR/ERβ/TPH2 pathway: GR acts as a transcription factor that binds to the ERβ promoter glucocorticoid response elements and inhibits ERβ transcription. Ahi1 regulates GR nuclear translocation (established in prior work), thereby modulating the ERβ/TPH2 serotonin synthesis pathway. Brain E2 (17β-estradiol) levels decrease in male but not female Ahi1-KO mice, explaining sex differences in depressive behavior. Western blot, gene knockdown, dual-luciferase reporter assay (GR binding to ERβ promoter), immunofluorescence, rescue assay (ERβ agonist), Ahi1-KO mouse, E2 measurement Cell communication and signaling : CCS Medium 35643536
2023 Mitochondrial Ahi1 and GR form a complex that, together with TFAM, regulates mtDNA copy number and brain ATP levels by binding to the D-loop control region of mitochondrial DNA. Loss of mitochondrial Ahi1/GR increases mtDNA copy numbers and decreases ATP levels. Regular exercise increases mitochondrial Ahi1/GR levels and improves depressive behavior in stressed but not Ahi1-KO mice. Co-immunoprecipitation (Ahi1/GR), ChIP-qPCR (GR binding to D-loop), Western blot (mitochondrial fractions), Ahi1-KO mouse, mtDNA copy number assay, ATP measurement Cell communication and signaling : CCS Medium 36691038
2025 In CEP290-null photoreceptors, AHI1 (normally a transition zone protein) is abnormally restricted to the proximal connecting cilium rather than distributed throughout the transition zone, indicating that CEP290 is required for proper spatial distribution of AHI1 within the connecting cilium. CEP290-null mouse retina, advanced microscopy (super-resolution), immunostaining for transition zone proteins bioRxivpreprint Low bio_10.1101_2025.01.20.633784

Source papers

Stage 0 corpus · 78 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 Abnormal cerebellar development and axonal decussation due to mutations in AHI1 in Joubert syndrome. Nature genetics 317 15322546
2004 Mutations in the AHI1 gene, encoding jouberin, cause Joubert syndrome with cortical polymicrogyria. American journal of human genetics 232 15467982
2010 AHI1 is required for photoreceptor outer segment development and is a modifier for retinal degeneration in nephronophthisis. Nature genetics 159 20081859
2007 High NPHP1 and NPHP6 mutation rate in patients with Joubert syndrome and nephronophthisis: potential epistatic effect of NPHP6 and AHI1 mutations in patients with NPHP1 mutations. Journal of the American Society of Nephrology : JASN 130 17409309
2010 Genetic screening of LCA in Belgium: predominance of CEP290 and identification of potential modifier alleles in AHI1 of CEP290-related phenotypes. Human mutation 116 20683928
2006 AHI1 gene mutations cause specific forms of Joubert syndrome-related disorders. Annals of neurology 104 16453322
2005 AHI1 mutations cause both retinal dystrophy and renal cystic disease in Joubert syndrome. Journal of medical genetics 92 16155189
2009 Ahi1, whose human ortholog is mutated in Joubert syndrome, is required for Rab8a localization, ciliogenesis and vesicle trafficking. Human molecular genetics 84 19625297
2008 Huntingtin-associated protein 1 interacts with Ahi1 to regulate cerebellar and brainstem development in mice. The Journal of clinical investigation 79 18636121
2008 Association of common variants in the Joubert syndrome gene (AHI1) with autism. Human molecular genetics 75 18782849
2005 Identification of the first AHI1 gene mutations in nephronophthisis-associated Joubert syndrome. Pediatric nephrology (Berlin, Germany) 69 16240161
2002 Ahi-1, a novel gene encoding a modular protein with WD40-repeat and SH3 domains, is targeted by the Ahi-1 and Mis-2 provirus integrations. Journal of virology 62 12186888
2006 AHI1, a pivotal neurodevelopmental gene, and C6orf217 are associated with susceptibility to schizophrenia. European journal of human genetics : EJHG 61 16773125
2008 AHI-1 interacts with BCR-ABL and modulates BCR-ABL transforming activity and imatinib response of CML stem/progenitor cells. The Journal of experimental medicine 60 18936234
2016 Common variants at PVT1, ATG13-AMBRA1, AHI1 and CLEC16A are associated with selective IgA deficiency. Nature genetics 55 27723758
2014 Cby1 promotes Ahi1 recruitment to a ring-shaped domain at the centriole-cilium interface and facilitates proper cilium formation and function. Molecular biology of the cell 52 25103236
2010 Retinal degeneration and failure of photoreceptor outer segment formation in mice with targeted deletion of the Joubert syndrome gene, Ahi1. The Journal of neuroscience : the official journal of the Society for Neuroscience 48 20592197
2022 Depression compromises antiviral innate immunity via the AVP-AHI1-Tyk2 axis. Cell research 43 35821088
2010 Neuronal Abelson helper integration site-1 (Ahi1) deficiency in mice alters TrkB signaling with a depressive phenotype. Proceedings of the National Academy of Sciences of the United States of America 42 20956301
2004 Deregulated expression in Ph+ human leukemias of AHI-1, a gene activated by insertional mutagenesis in mouse models of leukemia. Blood 42 14751929
2010 A large replication study and meta-analysis in European samples provides further support for association of AHI1 markers with schizophrenia. Human molecular genetics 40 20071346
2008 Species differences in the expression of Ahi1, a protein implicated in the neurodevelopmental disorder Joubert syndrome, with preferential accumulation to stigmoid bodies. The Journal of comparative neurology 36 18785627
2007 Support for involvement of the AHI1 locus in schizophrenia. European journal of human genetics : EJHG 36 17473831
2017 The Ciliopathy Gene ahi1 Is Required for Zebrafish Cone Photoreceptor Outer Segment Morphogenesis and Survival. Investigative ophthalmology & visual science 34 28118669
2019 Ciliary genes arl13b, ahi1 and cc2d2a differentially modify expression of visual acuity phenotypes but do not enhance retinal degeneration due to mutation of cep290 in zebrafish. PloS one 33 30970040
2007 DNA analysis of AHI1, NPHP1 and CYCLIN D1 in Joubert syndrome patients from the Netherlands. European journal of medical genetics 32 18054307
2009 Identification of tyrosine kinase, HCK, and tumor suppressor, BIN1, as potential mediators of AHI-1 oncogene in primary and transformed CTCL cells. Blood 31 19211505
2013 The Joubert syndrome-associated missense mutation (V443D) in the Abelson-helper integration site 1 (AHI1) protein alters its localization and protein-protein interactions. The Journal of biological chemistry 30 23532844
2010 Fine mapping of AHI1 as a schizophrenia susceptibility gene: from association to evolutionary evidence. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 30 20371615
2022 Ahi1 regulates serotonin production by the GR/ERβ/TPH2 pathway involving sexual differences in depressive behaviors. Cell communication and signaling : CCS 28 35643536
2006 Evidence for an oncogenic role of AHI-1 in Sezary syndrome, a leukemic variant of human cutaneous T-cell lymphomas. Leukemia 28 16838023
2015 Non-manifesting AHI1 truncations indicate localized loss-of-function tolerance in a severe Mendelian disease gene. Human molecular genetics 26 25616960
2013 Loss of Ahi1 affects early development by impairing BM88/Cend1-mediated neuronal differentiation. The Journal of neuroscience : the official journal of the Society for Neuroscience 26 23658157
2011 Modelling a ciliopathy: Ahi1 knockdown in model systems reveals an essential role in brain, retinal, and renal development. Cellular and molecular life sciences : CMLS 25 21959375
2013 Neural mechanisms underlying stress resilience in Ahi1 knockout mice: relevance to neuropsychiatric disorders. Molecular psychiatry 24 24042478
2021 Ahi1 regulates the nuclear translocation of glucocorticoid receptor to modulate stress response. Translational psychiatry 23 33782379
2018 Tyrosine hydroxylase down-regulation after loss of Abelson helper integration site 1 (AHI1) promotes depression via the circadian clock pathway in mice. The Journal of biological chemistry 23 29449373
2012 The role of AHI1 and CDKN1C in cutaneous T-cell lymphoma progression. Experimental dermatology 22 23171462
2010 Brainstem Hap1-Ahi1 is involved in insulin-mediated feeding control. FEBS letters 22 21146532
2023 The mitochondrial Ahi1/GR participates the regulation on mtDNA copy numbers and brain ATP levels and modulates depressive behaviors in mice. Cell communication and signaling : CCS 20 36691038
2010 Impact of the AHI1 gene on the vulnerability to schizophrenia: a case-control association study. PloS one 20 20805890
2017 Missense mutations in the WD40 domain of AHI1 cause non-syndromic retinitis pigmentosa. Journal of medical genetics 19 28442542
1994 The Myb and Ahi-1 genes are physically very closely linked on mouse chromosome 10. Mammalian genome : official journal of the International Mammalian Genome Society 18 7911043
2012 Investigating embryonic expression patterns and evolution of AHI1 and CEP290 genes, implicated in Joubert syndrome. PloS one 16 23028714
2010 Lymphoblast and brain expression of AHI1 and the novel primate-specific gene, C6orf217, in schizophrenia and bipolar disorder. Schizophrenia research 16 20452750
2019 Expression of AHI1 Rescues Amyloidogenic Pathology in Alzheimer's Disease Model Cells. Molecular neurobiology 15 31062249
2018 Effect of chronic unpredictable stress on mice with developmental under-expression of the Ahi1 gene: behavioral manifestations and neurobiological correlates. Translational psychiatry 15 29967406
2021 Stress modulates Ahi1-dependent nuclear localization of ten-eleven translocation protein 2. Human molecular genetics 14 34218273
2019 Ahi1 promotes Arl13b ciliary recruitment, regulates Arl13b stability and is required for normal cell migration. Journal of cell science 14 31391239
2017 The multiple sclerosis risk allele within the AHI1 gene is associated with relapses in children and adults. Multiple sclerosis and related disorders 14 29409597
2011 AHI-1: a novel signaling protein and potential therapeutic target in human leukemia and brain disorders. Oncotarget 14 22248740
2011 Hypothalamic Ahi1 mediates feeding behavior through interaction with 5-HT2C receptor. The Journal of biological chemistry 13 22123816
2021 The Transition Zone Protein AHI1 Regulates Neuronal Ciliary Trafficking of MCHR1 and Its Downstream Signaling Pathway. The Journal of neuroscience : the official journal of the Society for Neuroscience 12 33741721
2015 The influence of AHI1 variants on the diagnosis and treatment outcome in schizophrenia. International journal of molecular sciences 12 25622261
2012 Association of copy number variation in the AHI1 gene with risk of obesity in the Chinese population. European journal of endocrinology 11 22285701
2016 Alterations in the expression of a neurodevelopmental gene exert long-lasting effects on cognitive-emotional phenotypes and functional brain networks: translational evidence from the stress-resilient Ahi1 knockout mouse. Molecular psychiatry 10 27021817
2015 A homozygous AHI1 gene mutation (p.Thr304AsnfsX6) in a consanguineous Moroccan family with Joubert syndrome: a case report. Journal of medical case reports 10 26541515
2023 Common Risk Variants in AHI1 Are Associated With Childhood Steroid Sensitive Nephrotic Syndrome. Kidney international reports 9 37547536
2019 Mutant Ahi1 Affects Retinal Axon Projection in Zebrafish via Toxic Gain of Function. Frontiers in cellular neuroscience 9 30949029
2019 Loss of the neurodevelopmental Joubert syndrome causing protein, Ahi1, causes motor and muscle development delays independent of central nervous system involvement. Developmental biology 8 30695685
2009 Regulation of AHI1 expression in adult rat brain: Implication in hypothalamic feeding control. Biochemical and biophysical research communications 8 19819228
2021 Identification of a novel truncating variant in AHI1 gene and a brief review on mutations spectrum. Molecular biology reports 6 34191236
2019 Reduction of AHI1 in the serum of Taiwanese with probable Alzheimer's disease. Clinical biochemistry 5 31786207
2017 MS AHI1 genetic risk promotes IFNγ+ CD4+ T cells. Neurology(R) neuroimmunology & neuroinflammation 5 29379820
2016 A cis-eQTL in AHI1 confers risk to schizophrenia in European populations. Neuroscience letters 5 27585752
2012 Molecular and structural characterization of the SH3 domain of AHI-1 in regulation of cellular resistance of BCR-ABL(+) chronic myeloid leukemia cells to tyrosine kinase inhibitors. Proteomics 5 22623184
2018 Novel mutations of PKHD1 and AHI1 identified in two families with cystic renal disease. International journal of clinical and experimental pathology 4 31938409
2012 Expression changes of hypothalamic Ahi1 in mice brain: implication in sensing insulin signaling. Molecular biology reports 4 22740139
2009 Cloning and characterization of the promoter of the human AHI1 gene. Biochemical genetics 3 19191019
2022 Generation of an iPSC line from skin fibroblasts of a patient with Joubert syndrome carrying the homozygous loss of function variant c.787dupC in the AHI1 gene. Stem cell research 2 36521382
2009 Expression, purification, crystallization and preliminary X-ray crystallographic analysis of the SH3 domain of human AHI1. Acta crystallographica. Section F, Structural biology and crystallization communications 2 19342780
2008 Polymorphisms in AHI1 are not associated with type 2 diabetes or related phenotypes in Danes: non-replication of a genome-wide association result. Diabetologia 2 18227995
2021 AHI1 gene mutation in a consanguineous Iranian family affected by Joubert syndrome: A case report. Clinical case reports 1 34721863
2025 Gestational diabetes mellitus induces 5-HT system dysfunction and exacerbates an ASD-like phenotype in male offspring by inhibiting the Ahi1/B9D1/Shh axis. Brain, behavior, and immunity 0 41038357
2024 Blended Phenotypes of Sexual Development Disorder and Coenzyme Q10 Deficiency, Together with a Sibling with Homozygous Variants in the AHI1 Gene. Molecular syndromology 0 40475171
2021 Retinitis pigmentosa and molar tooth sign caused by novel AHI1 compound heterozygote pathogenic variants. BMC medical genomics 0 34627237
2017 The product of the human AHI-1 (Abelson helper integration site) gene: experimental in vitro data point to its involvement in tumor cell invasion. Annali dell'Istituto superiore di sanita 0 28361800
2009 [Expression and function of Ahi-1 gene in Jurkat cells]. Zhongguo shi yan xue ye xue za zhi 0 19379585

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