Affinage

KANSL1

KAT8 regulatory NSL complex subunit 1 · UniProt Q7Z3B3

Length
1105 aa
Mass
121.0 kDa
Annotated
2026-06-10
30 papers in source corpus 8 papers cited in narrative 9 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 4/5 claims corpus-supported (80%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

KANSL1 is an evolutionarily conserved scaffold subunit of the NSL histone acetyltransferase complex that directs KAT8-mediated histone H4 lysine 16 (H4K16) acetylation to regulate gene transcription (PMID:22544363, PMID:22544367, PMID:24788516). Within the complex it directly engages at least four other subunits, including WDR5, whose binding nucleates NSL complex assembly and recruitment to target promoters; this WDR5 interaction is mutually exclusive with WDR5's role in MLL/COMPASS, and KANSL1's PEHE domain contacts the KAT8 HAT domain (PMID:24788516, PMID:25621995). Beyond chromatin regulation, KANSL1 transcriptionally activates the autophagosomal SNARE gene STX17 to drive autophagosome-lysosome fusion and clearance of damaged mitochondria, with loss causing mitophagy defects and reactive oxygen species accumulation that are pharmacologically reversible by 13-cis retinoic acid (PMID:35177641). KANSL1 also supports hippocampal synaptic transmission (PMID:28704368), chondrocyte proliferation and cartilage matrix production (PMID:35727364), and motile ciliogenesis. Haploinsufficiency of KANSL1 is sufficient to cause the multi-system 17q21.31 microdeletion (Koolen-de Vries) syndrome and is the primary driver of its cognitive phenotypes (PMID:22544363, PMID:22544367, PMID:28704368).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2012 High

    Established KANSL1 as the dosage-sensitive gene behind the 17q21.31 microdeletion syndrome and linked it functionally to KAT8-dependent H4K16 acetylation and neuronal phenotypes.

    Evidence Human loss-of-function mutations, patient cell line RNA-seq, and Drosophila mutant behavioral assays, replicated across two labs

    PMID:22544363 PMID:22544367

    Open questions at the time
    • Did not resolve how KANSL1 is incorporated into or recruits the acetyltransferase machinery
    • Direct enzymatic or structural role of KANSL1 vs KAT8 not separated
  2. 2014 High

    Defined KANSL1 as the structural scaffold of the NSL complex, showing its direct WDR5 interaction is required for complex assembly, promoter recruitment, and viability.

    Evidence Biochemical interaction mapping, crystal structure of the KANSL1/WDR5/KANSL2 subcomplex, and structure-based mutagenesis in transgenic Drosophila

    PMID:24788516

    Open questions at the time
    • Identity of the specific target promoters in mammals not defined here
    • How NSL recruitment specificity is encoded remains unmapped
  3. 2017 High

    Demonstrated that KANSL1 haploinsufficiency alone reproduces the synaptic and cognitive deficits of the full deletion, pinpointing it as the primary driver of Koolen-de Vries cognitive phenotypes.

    Evidence Heterozygous Kansl1 mouse model with hippocampal electrophysiology, behavioral assays, and hippocampal transcriptomics

    PMID:28704368

    Open questions at the time
    • Direct chromatin targets driving synaptic dysregulation not identified
    • Cell-type-specific contributions not dissected
  4. 2022 High

    Extended KANSL1 function beyond chromatin by showing it transcriptionally controls STX17 to enable autophagosome-lysosome fusion and mitophagy, and that the resulting defects are pharmacologically reversible.

    Evidence siRNA screening, Kansl1+/- mouse mitophagy and ROS assays, STX17 transcriptional target identification, and 13-cis retinoic acid rescue

    PMID:35177641

    Open questions at the time
    • Whether STX17 regulation is direct NSL/H4K16ac-dependent not shown
    • Link between mitophagy defect and neurobehavioral phenotype is correlative
  5. 2022 Medium

    Implicated KANSL1 in skeletal development by showing it is required for chondrocyte proliferation and cartilage matrix production.

    Evidence Kansl1 missense mutant mouse histology and mouse ESC-derived chondrocyte differentiation assays with Mmp13 readout

    PMID:35727364

    Open questions at the time
    • Single lab
    • Mechanism connecting KANSL1 to Mmp13 dysregulation not defined
  6. 2024 Medium

    Added motile ciliogenesis to KANSL1's roles, with cross-species localization, depletion, rescue, and a human ciliary functional biomarker.

    Evidence Xenopus depletion with human KANSL1 rescue, ciliary localization imaging, and nasal nitric oxide measurement in KdVS patients (preprint)

    Open questions at the time
    • Preprint not yet peer-reviewed
    • Whether ciliary role requires NSL complex / H4K16ac activity unknown
  7. 2020 Medium

    Characterized KANSL1 as a 5' fusion partner in leukemogenesis, where its regulatory sequences drive aberrant MTCP1 expression.

    Evidence RNA-seq, RT-PCR, Sanger sequencing of a t(X;17) fusion and MTCP1 overexpression proliferation/differentiation assays

    PMID:32167630

    Open questions at the time
    • Disrupts KANSL1 regulatory region rather than revealing native KANSL1 function
    • Single case
  8. 2015 Medium

    Identified a KAT6B-KANSL1 fusion in leiomyoma retaining the KANSL1 PEHE domain that interacts with the KAT8 HAT domain.

    Evidence RNA-seq, RT-PCR, Sanger sequencing, and structural domain analysis of the fusion protein

    PMID:25621995

    Open questions at the time
    • No functional reconstitution of the fusion protein
    • Single case

Open questions

Synthesis pass · forward-looking unresolved questions
  • Whether KANSL1's diverse roles in autophagy, ciliogenesis, synaptic function, and chondrogenesis all stem from a single chromatin/H4K16ac transcriptional program or reflect distinct moonlighting functions remains unresolved.
  • Direct genome-wide NSL targets in mammals not mapped
  • Causal chain from H4K16ac to each tissue phenotype undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 3 GO:0042393 histone binding 1 GO:0060090 molecular adaptor activity 1
Localization
GO:0005634 nucleus 2 GO:0005929 cilium 1
Pathway
R-HSA-74160 Gene expression (Transcription) 3 R-HSA-4839726 Chromatin organization 2 R-HSA-9612973 Autophagy 1
Partners
KANSL2KAT8WDR5
Complex memberships
NSL (nonspecific lethal) histone acetyltransferase complex

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2012 KANSL1 protein is an evolutionarily conserved regulator of the chromatin modifier KAT8, which influences gene expression through histone H4 lysine 16 (H4K16) acetylation. Haploinsufficiency of KANSL1 is sufficient to cause the 17q21.31 microdeletion syndrome, and Drosophila melanogaster KANSL1 mutants exhibit learning deficits, suggesting a role in neuronal processes. Genetic haploinsufficiency (human loss-of-function mutations), RNA sequencing in patient-derived cell lines, Drosophila mutant behavioral assays Nature genetics High 22544363 22544367
2014 KANSL1 acts as a scaffold protein within the NSL complex, directly interacting with four other subunits including WDR5. WDR5 in turn binds KANSL2 via conserved linear motifs. Structure-based KANSL1 mutants in transgenic flies demonstrated that the KANSL1-WDR5 interaction is required for proper NSL complex assembly, efficient recruitment of the NSL complex to target promoters, and fly viability. WDR5 interactions with the NSL complex and MLL/COMPASS are mutually exclusive. Biochemical interaction mapping, crystal structure of KANSL1/WDR5/KANSL2 subcomplex, structure-based mutagenesis in transgenic Drosophila, chromatin recruitment assays Genes & development High 24788516
2022 KANSL1 modulates autophagosome-lysosome fusion for cargo degradation via transcriptional regulation of the autophagosomal SNARE gene STX17. Kansl1+/- mice exhibit impaired autophagic clearance of damaged mitochondria (mitophagy defects), accumulation of reactive oxygen species, and defective neuronal and cardiac functions. The FDA-approved drug 13-cis retinoic acid reverses these mitophagic and neurobehavioral defects by promoting autophagosome-lysosome fusion. siRNA screening, mechanistic studies in Kansl1+/- mice (STX17 transcriptional regulation, mitophagy assays, ROS measurement), pharmacological rescue with 13-cis retinoic acid Nature communications High 35177641
2017 Heterozygous loss-of-function of Kansl1 in mice causes synaptic transmission defects in the hippocampus, as well as upregulation of genes controlling chromatin organization, synaptic transmission, and neurogenesis. Kansl1+/- mice display behavioral and anatomical phenotypes similar to the full 17q21.31 deletion model, establishing KANSL1 as the primary driver of cognitive phenotypes in Koolen-de Vries syndrome. Heterozygous Kansl1 mouse model, hippocampal electrophysiology (synaptic transmission), behavioral assays, hippocampal transcriptomics PLoS genetics High 28704368
2022 KANSL1 is required for chondrocyte proliferation and cartilage matrix production; Kansl1-mutated mice show reduced chondrocytes in the acetabulum, decreased cartilage matrix, and Kansl1 mutant mouse embryonic stem cell-derived chondrocytes exhibit delayed cell proliferation and abnormally upregulated Mmp13 expression. Mouse Kansl1 missense mutant model, histological analysis, mouse embryonic stem cell chondrocyte differentiation assay, gene expression analysis (Mmp13) Journal of molecular medicine (Berlin, Germany) Medium 35727364
2024 KANSL1 is required for motile ciliogenesis; Kansl1 is highly expressed in developing ciliated tissues in Xenopus and localizes within motile cilia. Kansl1 depletion causes ciliogenesis defects that are partially rescued by human KANSL1. In human KdVS patients, nasal nitric oxide (a ciliary functional biomarker) is significantly decreased compared to unaffected family members. Xenopus loss-of-function (morpholino/depletion), live imaging/localization within motile cilia, rescue with human KANSL1, nasal nitric oxide measurement in KdVS patients bioRxiv (preprint)preprint Medium
2020 A chromosomal translocation t(X;17)(q28;q21) in acute monocytic leukemia generates a KANSL1-MTCP1 fusion in which the 5'-UTR sequences of KANSL1 become fused upstream of the MTCP1 coding sequence, resulting in aberrantly high MTCP1 expression. Overexpression of MTCP1 induced increased cell proliferation and partial blockage of cell differentiation, implicating dysregulated MTCP1 as critical in leukemogenesis. RNA sequencing, RT-PCR, Sanger sequencing, functional overexpression assays (proliferation and differentiation) Genes, chromosomes & cancer Medium 32167630
2015 A t(10;17)(q22;q21) chromosomal rearrangement in retroperitoneal leiomyoma generates a KAT6B-KANSL1 fusion transcript consisting of KAT6B exons 1-3 fused to KANSL1 exons 11-15, encoding a 466 amino acid protein containing the NEMM/linker histone domain of KAT6B and the PEHE domain of KANSL1 (which interacts with the HAT domain of KAT8). RNA sequencing, RT-PCR, Sanger sequencing, structural domain analysis of fusion protein PloS one Medium 25621995
2033 17q21.31 H1 haplotype variation (linked to KANSL1) downregulates autophagy, lysosomal, and mitochondrial gene expression pathways in brain; siRNA knockdown of KANSL1 in neuronal and glial human cell lines recapitulates these transcriptional effects, and in glial cells is associated with modulation of innate and adaptive immune responses. Bulk and single-nuclear RNA-sequencing of human brain tissue across haplotype groups; siRNA knockdown of KANSL1 in neuronal and glial human cell lines with transcriptome analysis bioRxiv (preprint)preprint Low

Source papers

Stage 0 corpus · 30 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 Mutations in the chromatin modifier gene KANSL1 cause the 17q21.31 microdeletion syndrome. Nature genetics 185 22544363
2012 Mutations in KANSL1 cause the 17q21.31 microdeletion syndrome phenotype. Nature genetics 124 22544367
2015 The Koolen-de Vries syndrome: a phenotypic comparison of patients with a 17q21.31 microdeletion versus a KANSL1 sequence variant. European journal of human genetics : EJHG 110 26306646
2014 Structural analysis of the KANSL1/WDR5/KANSL2 complex reveals that WDR5 is required for efficient assembly and chromatin targeting of the NSL complex. Genes & development 99 24788516
2022 Kansl1 haploinsufficiency impairs autophagosome-lysosome fusion and links autophagic dysfunction with Koolen-de Vries syndrome in mice. Nature communications 40 35177641
2015 Intragenic KANSL1 mutations and chromosome 17q21.31 deletions: broadening the clinical spectrum and genotype-phenotype correlations in a large cohort of patients. Journal of medical genetics 39 26424144
2015 Novel KAT6B-KANSL1 fusion gene identified by RNA sequencing in retroperitoneal leiomyoma with t(10;17)(q22;q21). PloS one 34 25621995
2015 KANSL1 gene disruption associated with the full clinical spectrum of 17q21.31 microdeletion syndrome. BMC medical genetics 32 26293599
2022 Recurrent KAT6B/A::KANSL1 Fusions Characterize a Potentially Aggressive Uterine Sarcoma Morphologically Overlapping With Low-grade Endometrial Stromal Sarcoma. The American journal of surgical pathology 29 35575789
2017 Partial microduplication in the histone acetyltransferase complex member KANSL1 is associated with congenital heart defects in 22q11.2 microdeletion syndrome patients. Scientific reports 26 28496102
2017 Mouse models of 17q21.31 microdeletion and microduplication syndromes highlight the importance of Kansl1 for cognition. PLoS genetics 25 28704368
2023 The KAT6B::KANSL1 Fusion Defines a New Uterine Sarcoma With Hybrid Endometrial Stromal Tumor and Smooth Muscle Tumor Features. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 23 37307879
2020 Analysis in epithelial ovarian cancer identifies KANSL1 as a biomarker and target gene for immune response and HDAC inhibition. Gynecologic oncology 21 33229045
2019 Leiomyoma with KAT6B-KANSL1 fusion: case report of a rapidly enlarging uterine mass in a postmenopausal woman. Diagnostic pathology 16 31027501
2024 Uterine mesenchymal tumours harboring the KAT6B/A::KANSL1 gene fusion represent a distinct type of uterine sarcoma based on DNA methylation profiles. Virchows Archiv : an international journal of pathology 11 39392508
2020 Adult phenotype in Koolen-de Vries/KANSL1 haploinsufficiency syndrome. Journal of medical genetics 9 33361104
2024 A new blood DNA methylation signature for Koolen-de Vries syndrome: Classification of missense KANSL1 variants and comparison to fibroblast cells. European journal of human genetics : EJHG 8 38282074
2022 Identification of KANSL1 as a novel pathogenic gene for developmental dysplasia of the hip. Journal of molecular medicine (Berlin, Germany) 8 35727364
2022 Next-generation phenotyping contributing to the identification of a 4.7 kb deletion in KANSL1 causing Koolen-de Vries syndrome. Human mutation 7 36104871
2020 Clinical Genetics Can Solve the Pitfalls of Genome-Wide Investigations: Lesson from Mismapping a Loss-of-Function Variant in KANSL1. Genes 7 33050294
2024 Uterine sarcoma with KAT6B/A::KANSL1 fusion: a molecular and clinicopathological study on 9 cases. Virchows Archiv : an international journal of pathology 5 39627614
2017 10-year-old female with intragenic KANSL1 mutation, no KANSL1-related intellectual disability, and preserved verbal intelligence. American journal of medical genetics. Part A 5 28211987
2024 Late relapse of chronic myeloid leukemia after allogeneic bone marrow transplantation points to KANSARL (KANSL1::ARL17A) alteration: a case report with insights on the molecular landscape. Annals of hematology 4 38321229
2020 Identification of a t(X;17)(q28;q21) generating a KANSL1-MTCP1 gene fusion leading to dysregulated expression of MTCP1 in acute myeloid leukemia. Genes, chromosomes & cancer 4 32167630
2022 Koolen-de Vries syndrome: A de novo missense KANSL1 variant. Clinical neurology and neurosurgery 3 36150256
2022 MDS/MPN-Unclassifiable with t(X;17)(q28;q21) and KANSL1-MTCP1/CMC4 Fusion Gene. Cytogenetic and genome research 2 35038703
2024 Clinical and genetic characteristics of a case of Koolen-De Vries syndrome caused by KANSL1 gene mutation and literature review: A case report. Medicine 1 39654190
2026 The KANSL1-ARL17A fusion gene generates oncogenic chKANSARL and F-circKA RNAs that synergistically drive lung cancer progression via a novel F-circKA/miR-6860/chKANSARL axis. The Journal of biological chemistry 0 41570994
2025 De Novo HNRNPU Pathogenic Variant Related to Developmental Epileptic Encephalopathy With Inherited KANSL1 Loss-of-Function Variant Resolved by RNA Analysis. Molecular genetics & genomic medicine 0 40923359
2025 circKANSL1 promotes immature porcine Sertoli cell growth via recruiting the Vimentin to enhance its parental gene KANSL1 expression. Theriogenology 0 41297216

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