Evidence map›Paper›PMID 41408595›Full record

ArticleBrain : a journal of neurology2026

A functional role for Septin-2 in the maintenance of the axon initial segment and in human cognitive development.

Luisa Weiss, Macarena Pavez, Anastasia Labudina, Liliia Andriichuk, Owen Jones, Amy Jones, Deanna Barwick, Zandra Jenkins, Indranil Basak, Tim Morgan and 15 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Brain : a journal of neurology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

0numbers the graph read from it
0cells of the map it votes in
0citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

0 citing papers in PubMed.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

25 authors.

Luisa WeissLaboratory for Genomic Medicine, Paediatrics and Child Health, Dunedin School of Medicine, University of Otago, Dunedin 9016, New Zealand.
Macarena PavezDepartment of Anatomy, University of Otago, Dunedin 9016, New Zealand.
Anastasia LabudinaLaboratory for Genomic Medicine, Paediatrics and Child Health, Dunedin School of Medicine, University of Otago, Dunedin 9016, New Zealand.
Liliia AndriichukNeuroscience Center, Helsinki Institute of Life Science, University of Helsinki, Helsinki 00014, Finland.
Owen JonesDepartment of Psychology, University of Otago, Dunedin 9016, New Zealand.
Amy JonesLaboratory for Genomic Medicine, Paediatrics and Child Health, Dunedin School of Medicine, University of Otago, Dunedin 9016, New Zealand.
Deanna BarwickDepartment of Anatomy, University of Otago, Dunedin 9016, New Zealand.
Zandra JenkinsLaboratory for Genomic Medicine, Paediatrics and Child Health, Dunedin School of Medicine, University of Otago, Dunedin 9016, New Zealand.
Indranil BasakDepartment of Biochemistry, University of Otago, Dunedin 9016, New Zealand.
Tim MorganLaboratory for Genomic Medicine, Paediatrics and Child Health, Dunedin School of Medicine, University of Otago, Dunedin 9016, New Zealand.
Teresa NeuhannMedical Genetics Center, MGZ-Medizinisch Genetisches Zentrum München, München 80335, Germany.
Julia RankinPeninsula Clinical Genetics Service, Royal Devon University Hospital, Exeter EX2 5DW, UK.
Jacques GiltayDivision Laboratories, Pharmacy and Biomedical Genetics, Genetics Department, University Medical Center Utrecht, Utrecht 3584 CX, Netherlands.
Emanuele AgoliniLaboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Gesù Children Hospital, IRCCS, Rome 00146, Italy.ORCID 0000-0001-6543-6225
Antonio NovelliLaboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Gesù Children Hospital, IRCCS, Rome 00146, Italy.
Antonio PizzutiDepartment of Experimental Medicine, Sapienza University of Rome, Rome 00185, Italy.
Daniel C KoboldtSteve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH 43205, USA.
Swetha RamadesikanSteve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH 43205, USA.
Leeran B Dublin-RyanSteve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH 43205, USA.
Stephanie HughesDepartment of Biochemistry, University of Otago, Dunedin 9016, New Zealand.
Nataylia Di DonatoInstitute for Human Genetics, MHH Hannover, Hannover 30625, Germany.
Greg GimenezDepartment of Pathology, University of Otago, Dunedin 9016, New Zealand.
Takashi NambaNeuroscience Center, Helsinki Institute of Life Science, University of Helsinki, Helsinki 00014, Finland.
Laura F GumyDepartment of Anatomy, University of Otago, Dunedin 9016, New Zealand.
Stephen P RobertsonLaboratory for Genomic Medicine, Paediatrics and Child Health, Dunedin School of Medicine, University of Otago, Dunedin 9016, New Zealand.

Funding

Curekids New ZealandDaiichi Sankyo Foundation of Life ScienceERA-Net NEURONFujita Health UniversityGerman Research FoundationJapan Spina Bifida & Hydrocephalus Research FoundationMarsden FundResearch Council of FinlandSigrid Jusélius FoundationSustainable Wellbeing Across LifespanUniversity of Helsinki
6 · The paper itself

Abstract

The establishment of neuronal polarity, whereby somatodendritic and axonal cellular compartments are defined, is a critical determinant for the development of neuronal networks and patterning during neurogenesis. The axon initial segment (AIS), a key structure in the establishment of this polarity, is formed through interactions between the microtubule and actin cytoskeleton, Ankyrin G, TRIM46 and multiple transmembrane and perimembranous proteins. Here, we implicate a component of the septin cytoskeleton, Septin-2, in the maintenance and function of the AIS through the study of mutations found in five unrelated human individuals and one mother-daughter duo with a majority presenting with cognitive impairment. Septins form octameric rods that assemble into higher-order filamentous scaffolds driven by Septin-2 homodimerization. Mutant Septin-2 is predicted to impart a dominant negative blockade on septin octamers forming these structures by precluding Septin-2 homodimerization. Expression of mutant Septin-2 constructs in neurons leads to the disappearance of canonical hallmarks of the AIS. This includes loss of Ankyrin G in the AIS, aberrant localization of MAP2 within the distal axon, axonal shortening and electrophysiological hypoexcitability. We further show that Septin-2 binds to a neuron-specific domain of Ankyrin G, an interaction that is largely ablated by these mutations. These data establish a role for Septin-2 in the maintenance and function of the AIS and implicate cytoskeletal structures composed of septin oligomers in the establishment of higher cognitive functions in humans.

Indexed as

Axon Initial SegmentAxonsSeptinsAnimalsCells, CulturedFemaleHumansMutationNeuronsSEPTIN2 protein, humanSeptinsaxon initial segmentneurodevelopmentSeptin-2

Identifiers

PMID41408595
PMCPMC13337235

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.