Evidence map›Paper›PMID 32873342›Full record

ArticleMolecular autism2020

Autism-associated variants of neuroligin 4X impair synaptogenic activity by various molecular mechanisms.

Takafumi Yumoto, Misaki Kimura, Ryota Nagatomo, Tsukika Sato, Shun Utsunomiya, Natsue Aoki, Motoji Kitaura, Koji Takahashi, Hiroshi Takemoto, Hirotaka Watanabe and 4 more

Open access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Molecular autism, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
5citing papers in PubMed, 1 pooled it
0.5field-weighted citation impact, top 28% of its field
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

5 citing papers in PubMed, 1 synthesis or guideline pooled it, 7 citations in OpenAlex.

  1. Pooled it
  2. Review
  3. Review
  4. Review
  5. Article
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

14 authors at 3 institutions in 1 country.

Takafumi YumotoLaboratory of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
Misaki KimuraLaboratory of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
Ryota NagatomoLaboratory of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
Tsukika SatoDepartment of Physiology, Keio University School of Medicine, Tokyo, Japan.
Shun UtsunomiyaNeuroscience 2, Laboratory for Drug Discovery and Disease Research, Shionogi, Osaka, Japan.
Natsue AokiNeuroscience 2, Laboratory for Drug Discovery and Disease Research, Shionogi, Osaka, Japan.
Motoji KitauraResearch Administration SPRC, R&D General Administration Unit, General Administration Division, Shionogi Administration Service, Osaka, Japan.
Koji TakahashiDrug Discovery Technology 3, Laboratory for Innovative Therapy Research, Shionogi, Osaka, Japan.
Hiroshi TakemotoNeuroscience 2, Laboratory for Drug Discovery and Disease Research, Shionogi, Osaka, Japan.
Hirotaka WatanabeDepartment of Physiology, Keio University School of Medicine, Tokyo, Japan.
Hideyuki OkanoDepartment of Physiology, Keio University School of Medicine, Tokyo, Japan.
Fumiaki YoshidaLaboratory of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
Yosuke NaoLaboratory of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
Taisuke TomitaLaboratory of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan. taisuke@mol.f.u-tokyo.ac.jp.ORCID 0000-0002-0075-5943
The University of Tokyo · JPShionogi (Japan) · JPKeio University · JP

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

backgroundSeveral genetic alterations, including point mutations and copy number variations in NLGN genes, have been associated with psychiatric disorders, such as autism spectrum disorder (ASD) and X-linked mental retardation (XLMR). NLGN genes encode neuroligin (NL) proteins, which are adhesion molecules that are important for proper synaptic formation and maturation. Previously, we and others found that the expression level of murine NL1 is regulated by proteolytic processing in a synaptic activity-dependent manner.

methodsIn this study, we analyzed the effects of missense variants associated with ASD and XLMR on the metabolism and function of NL4X, a protein which is encoded by the NLGN4X gene and is expressed only in humans, using cultured cells, primary neurons from rodents, and human induced pluripotent stem cell-derived neurons.

resultsNL4X was found to undergo proteolytic processing in human neuronal cells. Almost all NL4X variants caused a substantial decrease in the levels of mature NL4X and its synaptogenic activity in a heterologous culture system. Intriguingly, the L593F variant of NL4X accelerated the proteolysis of mature NL4X proteins located on the cell surface. In contrast, other variants decreased the cell-surface trafficking of NL4X. Notably, protease inhibitors as well as chemical chaperones rescued the expression of mature NL4X. LIMITATIONS: Our study did not reveal whether these dysfunctional phenotypes occurred in individuals carrying NLGN4X variant. Moreover, though these pathological mechanisms could be exploited as potential drug targets for ASD, it remains unclear whether these compounds would have beneficial effects on ASD model animals and patients.

conclusionsThese data suggest that reduced amounts of the functional NL4X protein on the cell surface is a common mechanism by which point mutants of the NL4X protein cause psychiatric disorders, although different molecular mechanisms are thought to be involved. Furthermore, these results highlight that the precision medicine approach based on genetic and cell biological analyses is important for the development of therapeutics for psychiatric disorders.

Indexed as

Amino Acid SequenceAnimalsAutistic DisorderCell Adhesion Molecules, NeuronalCell MembraneCells, CulturedGenetic Predisposition to DiseaseHEK293 CellsHumansInduced Pluripotent Stem CellsMiceMutationMutation, MissenseNeuronsOrganogenesisRats, WistarCell Adhesion Molecules, NeuronalNLGN4X protein, humanNeuroligin 4XProteolysisSynaptogenesisTrafficking

Identifiers

PMID32873342
PMCPMC7465329
OpenAlexW3082451282

What OpenQuestion holds

Textmetadata
LicenceCC BY
Read underepoch 390

Registered trials

None linked

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.