Neuron - the off-target cell type that defines what KANSL1 loss costs a human being
also called neuron · nerve cell · hiPSC-derived cortical neuron · cortical neuron
A neuron is the cell that carries electrical signals in the brain. It matters to a leukaemia graph because losing one working copy of KANSL1 - a protein in a complex this project tracks inside the fusion interactome - causes a neurodevelopmental syndrome in people, which is the clearest measurement anywhere of what turning KANSL1 down would cost.
The same thing, for a scientist
The neuron (CL:0000540) is included here as an **off-target cell type with a measured human loss-of-function phenotype**, not as a site of leukaemia biology. Haploinsufficiency of `KANSL1`, the scaffold of the NSL complex this graph carries as part of the KAT8/MOF layer, causes **Koolen-de Vries syndrome** (KdVS). In hiPSC-derived neurons from KdVS patients on microelectrode arrays, networks show reduced burst rates and increased variability in burst rhythmicity, with impaired mitochondrial function and reduced synaptic density; the antioxidant phloretin partially rescues the network phenotype, reactive oxygen species and synaptic density across patient lines [E1]. In mice, `Kansl1` heterozygosity impairs autophagosome-lysosome fusion via transcriptional control of STX17, causing defective clearance of damaged mitochondria, ROS accumulation and defective neuronal and cardiac function, reversible with 13-cis retinoic acid [E2]. Two independent systems, one human and one murine, converge on a **mitochondrial-quality-control defect in neurons at half gene dosage** - which is the single hardest constraint on any therapeutic strategy that would lower KANSL1.
Why this cell type is in this graph
Because a bite-back argument needs a number, and this is where the number is.
When this graph proposes reducing a chromatin regulator, the standard objection is essential-function toxicity, and it is usually argued from mouse knockouts or from gnomAD constraint. The brief already warns that a constraint score is not a safety signal for pharmacological inhibition. KANSL1 is the rare case where the human experiment has been done: a defined, named syndrome caused by heterozygous loss, with a described neuronal cellular phenotype. That is stronger and more specific than any constraint metric, and it is a property of the neuron, not of the blast.
The graph already carries non-haematopoietic cell types where they are load-bearing - cell-type-bone-marrow-sympathetic-nerve is one - so a neuron node is not a category departure.
What the two systems show, and how they differ
Human, hiPSC-derived neurons from KdVS patients 1. Reduced network burst rate and increased burst-rhythmicity variability on microelectrode arrays. Integrating electrophysiology with transcriptome profiling (MEA-seq) found a negative correlation between the neurodevelopmental gene CLCN4 and burst rate, and CLCN4 knockdown in KdVS neurons moved bursting back toward control. Mitochondrial gene expression correlated with network activity and mitochondrial function was confirmed impaired. Computational screening against LINCS nominated compounds, of which phloretin improved network activity, reduced reactive oxygen species and rescued synaptic density.
Mouse, Kansl1+/- 2. KANSL1 was identified in an siRNA screen as required for autophagy; it controls autophagosome-lysosome fusion by transcriptionally regulating STX17. Heterozygous mice fail to clear damaged mitochondria, accumulate ROS, and show defective neuronal and cardiac function; 13-cis retinoic acid reverses the mitophagic defect and the neurobehavioural abnormalities.
What is shared is the mitochondrial half. Both point at damaged-mitochondria handling at half dosage. What is not shared is the mechanism proposed for it - a transcriptional autophagy defect in one, an unspecified mitochondrial impairment correlated with network activity in the other - and neither paper tests the other's model. The convergence is therefore on the phenotype, not on the pathway.
Note the cardiac finding in 2. It is not a neuron result and is recorded here only because it comes from the same animals; it widens the off-target surface rather than narrowing it.
What this does NOT say
It does not say that KANSL1 has a role in leukaemia, and it does not licence borrowing an NSL-complex result from another subunit. Measured 2026-09-21: KANSL1[tiab] returns 179 records and KANSL1[tiab] AND (KMT2A[tiab] OR MLL[tiab]) returns 2; (KANSL1[tiab] OR "KAT8 regulatory NSL"[tiab]) AND (hematopoie*[tiab] OR haematopoie*[tiab] OR leukemia[tiab] OR leukaemia[tiab] OR "bone marrow"[tiab] OR "B cell"[tiab]) returns 6. Zero of those is a KANSL1 cell-type or cell-state experiment in a haematopoietic cell. Zero in titles and abstracts; supporting figures not searched.
The haematopoietic results that do exist belong to KAT8/MOF, a different subunit of the same complex, and the graph's own rule 64 exists precisely to stop a complex-level result being written onto a subunit. They are recorded on gene-kansl1 as complex-level context and explicitly not attributed.
| ontology | CL:0000540 |
|---|---|
| why in this graph | off-target cell type carrying the measured human loss-of-function phenotype of KANSL1, an NSL-complex subunit in the fusion interactome layer |
| evidence class | maintains_a_state (neuronal network and mitochondrial-quality-control competence at full gene dosage). NOT a dependency: KANSL1-haploinsufficient neurons are alive. |
| shown for fusion | NO, and not applicable - this cell type is recorded for the toxicity argument, not for fusion biology. Measured 2026-09-21: KANSL1[tiab] = 179; KANSL1[tiab] AND (KMT2A[tiab] OR MLL[tiab]) = 2; KANSL1 or 'KAT8 regulatory NSL' against a haematopoietic term = 6, none of them a cell-type or cell-state experiment. Zero in titles and abstracts; supporting figures not searched. |
| scope caution | Constitutional half-dosage from conception is not the same exposure as partial reversible inhibition in an adult. This node states what the human genetics shows, not what a drug would do. |
human loss of function phenotype
{
"syndrome": "Koolen-de Vries syndrome (KdVS)",
"genetics": "KANSL1 haploinsufficiency, by 17q21.31 microdeletion or by intragenic loss-of-function variant",
"cellular_phenotype_human": "reduced network burst rate and increased burst-rhythmicity variability in hiPSC-derived neurons; impaired mitochondrial function; reduced synaptic density",
"cellular_phenotype_mouse": "impaired autophagosome-lysosome fusion via STX17; failed clearance of damaged mitochondria; ROS accumulation; defective neuronal AND cardiac function"
}- ESSENTIAL-FUNCTION TOXICITY — This is the entry's whole point. Reducing KANSL1 to roughly half its level produces a named human neurodevelopmental syndrome. Any strategy that would lower KANSL1 in an infant - the population this graph is about, and the population whose brain is still being built - has to answer that directly, and no potency or selectivity argument answers it, because the phenotype is caused by dosage rather than by complete loss.
- DELIVERY — The constraint would be relaxed by an agent that does not cross the blood-brain barrier, but infant KMT2A-rearranged leukaemia has a real CNS burden and CNS-directed therapy is standard, so a deliberately CNS-sparing agent conflicts with where the disease goes.
- COMPENSATION — 13-cis retinoic acid reversed the murine mitophagic and neurobehavioural defects, and phloretin improved the human neuronal network phenotype. If either generalises, the toxicity may be pharmacologically manageable rather than absolute - but both are single reports in disease models, not co-administration studies alongside a KANSL1-lowering agent, and neither has been tested in the presence of leukaemia therapy.
- Both systems land on damaged-mitochondria handling but propose different routes to it - STX17-dependent autophagosome-lysosome fusion in mouse, an unspecified mitochondrial impairment plus CLCN4 in human neurons. Does STX17 expression track KANSL1 dosage in the human KdVS iPSC neurons? One qPCR would test whether these are one mechanism or two.
- Is the mitochondrial-quality-control defect neuron-specific or a general consequence of KANSL1 half-dosage? If it is general, then a haematopoietic cell at half dosage should show it too, and the absence of any KANSL1 haematopoietic phenotype in the literature becomes a genuine question rather than a gap in attention.
- Does the graph need equivalent human loss-of-function cell-type entries for its other proposed targets? KANSL1 is unusual in having one; most of the interactome is argued from mouse knockouts and constraint scores.
- E1strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
hiPSC-derived neurons from Koolen-de Vries syndrome patients, who carry KANSL1 haploinsufficiency, show reduced network burst rates and increased variability in burst rhythmicity on microelectrode arrays, together with impaired mitochondrial function and reduced synaptic density; the antioxidant phloretin improved multiple aspects of the network phenotype, reduced reactive oxygen species and rescued synaptic density across patient lines.
Integrative transcriptomics and electrophysiological profiling of hiPSC-derived neurons identifies novel druggable pathways in Koolen-de Vries Syndrome. · Verboven AHA, Puvogel S, Latour BL, Kolsters N, Lewerissa EI, Mijdam R, Dyke E, Duineveld D, Zoodsma M, Claassen WJJ, Oudakker A, Schoenmaker C, Koolen DA, de Vries BBA, 't Hoen PAC, Linda K, Nadif Kasri N · Mol Psychiatry 2026What this evidence cannot show
Human iPSC-derived neurons cultured on microelectrode arrays, which is a reductionist model of a cortical network and not a brain. The drug nomination step is a computational LINCS signature screen with ten candidates triaged, so phloretin is a hit from a prioritised list rather than a mechanism-first choice. Read: abstract only. Nothing here is a leukaemia, haematopoietic or KMT2A-rearranged system.
Evidence that argues against this (1)
- A network-level electrophysiological phenotype in cultured neurons is several steps from the clinical syndrome, and the mechanism proposed here (CLCN4, mitochondrial gene expression) is not the mechanism proposed by the murine work on the same gene, which attributes the neuronal defect to failed autophagosome-lysosome fusion through STX17. Two models of one phenotype, neither testing the other. Li T et al. 2022
- E2strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
In mice, Kansl1 haploinsufficiency impairs autophagosome-lysosome fusion through transcriptional regulation of STX17, causing failure to clear damaged mitochondria, accumulation of reactive oxygen species, and defective neuronal and cardiac function; 13-cis retinoic acid reverses the mitophagic defect and the neurobehavioural abnormalities.
Kansl1 haploinsufficiency impairs autophagosome-lysosome fusion and links autophagic dysfunction with Koolen-de Vries syndrome in mice. · Li T, Lu D, Yao C, Li T, Dong H, Li Z, Xu G, Chen J, Zhang H, Yi X, Zhu H, Liu G, Wen K, Zhao H, Gao J, Zhang Y, Han Q, Li T, Zhang W, Zhao J, Li T, Bai Z, Song M, He X, Zhou T, Xia Q, Li A, Pan X · Nat Commun 2022What this evidence cannot show
Mouse heterozygote plus an siRNA screen in cell lines. Lifelong constitutional half-dosage from conception, which is a different exposure from partial reversible pharmacological inhibition in an adult or a child - the database-scope caution in the standing brief applies here as much as it does to gnomAD constraint. Read: abstract only.
Evidence that argues against this (1)
- The human iPSC-neuron work on the same haploinsufficiency attributes the neuronal phenotype to mitochondrial dysfunction correlated with network activity and to CLCN4, and rescues it with an antioxidant rather than by restoring autophagic flux. The phenotypes converge; the proposed pathways do not. Verboven AHA et al. 2026
KANSL1 haploinsufficiency (Koolen-de Vries syndrome) impairs neuronal network bursting, mitochondrial function and synaptic density in patient hiPSC-derived neurons, and mitophagy and neuronal function in Kansl1+/- mice; the human loss-of-function phenotype that constrains any KANSL1-lowering strategy
- ← expressed inTOP2B - the isoform most etoposide-induced KMT2A breaks depend on, resolved genetically and not resolvable pharmacologically
Top2b is required in postmitotic neurons for motor and sensory axon growth while neurogenesis itself is normal (murine germline mutant; PMID 10615047)
- ← regulatesHCFC1 (HCF-1) — a founding member of the wild-type KMT2A complex that the fusion cannot bind
the only organism-level cell-type consequence documented for HCFC1 is neural: overexpression increases astrocyte production and reduces neurite growth in murine embryonic neural stem cells and hippocampal neurons, with X-linked intellectual disability in the families (PMID 23000143)