Evidence mapPaperPMID 42098603Full record

ArticleMolecular medicine (Cambridge, Mass.)2026

Identification of the adhesion GPCR ADGRL4/ELTD1 as a novel potential prognostic biomarker for cerebral cavernous malformation disease.

Andrea Perrelli, Ashraqat Ahmed, Anna Onisiforou, Gwenola Boulday, Juan Zalvide, Celia M Pombo, José E Martínez, Alessio Paolini, Salim Abdelilah-Seyfried, Ioannis Petrakakis and 10 more

Abstract read
In one paragraph

Article in Molecular medicine (Cambridge, Mass.), 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

20 authors.

Andrea PerrelliDepartment of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, NY, 14642, USA.
Ashraqat AhmedInternational Neuroscience Institute, Rudolf-Pichlmayr-Strasse 4, Hannover, 30625, Germany.
Anna OnisiforouDepartment of Psychology, University of Cyprus, Nicosia, 1057, Cyprus.
Gwenola BouldayInstitut du Cerveau Et de La Moelle Épinière, ICM, Inserm U1127, CNRS UMR 7225, Sorbonne Université, Paris, 75013, France.
Juan ZalvideDepartment of Physiology, Centro Singular de Medicina Molecular E Enfermedades Crónicas (CiMUS), Instituto Sanitario de Santiago de Compostela (IDIS), Universidade de Santiago de Compostela, A Coruña, Spain.
Celia M PomboDepartment of Physiology, Centro Singular de Medicina Molecular E Enfermedades Crónicas (CiMUS), Instituto Sanitario de Santiago de Compostela (IDIS), Universidade de Santiago de Compostela, A Coruña, Spain.
José E MartínezDepartment of Physiology, Centro Singular de Medicina Molecular E Enfermedades Crónicas (CiMUS), Instituto Sanitario de Santiago de Compostela (IDIS), Universidade de Santiago de Compostela, A Coruña, Spain.
Alessio PaoliniInstitute of Biochemistry and Biology, Universität Potsdam, Karl-Liebknecht Strasse 24-25, Potsdam-Golm, 14476, Germany.
Salim Abdelilah-SeyfriedInstitute of Biochemistry and Biology, Universität Potsdam, Karl-Liebknecht Strasse 24-25, Potsdam-Golm, 14476, Germany.
Ioannis PetrakakisInternational Neuroscience Institute, Rudolf-Pichlmayr-Strasse 4, Hannover, 30625, Germany.
Wolfram S KunzInstitute of Experimental Epileptology and Cognition Research and Department of Epileptology, University Hospital Bonn, Venusberg-Campus 1, Bonn, 53127, Germany.
Robert GeffersGenome Analytics, Helmholtz Centre for Infection Research, Brunswick, 38124, Germany.
Christian HartmannDepartment of Neuropathology, Institute of Pathology, Hannover Medical School, Carl-Neuberg-Straße 1, Hannover, 30625, Germany.
Walter BiniInternational Neuroscience Institute, Rudolf-Pichlmayr-Strasse 4, Hannover, 30625, Germany.
Gerasimos BaltsaviasInternational Neuroscience Institute, Rudolf-Pichlmayr-Strasse 4, Hannover, 30625, Germany.
Amir SamiiInternational Neuroscience Institute, Rudolf-Pichlmayr-Strasse 4, Hannover, 30625, Germany.
Helmut BertalanffyInternational Neuroscience Institute, Rudolf-Pichlmayr-Strasse 4, Hannover, 30625, Germany.
Saverio F RettaDepartment of Clinical and Biological Sciences, University of Torino, Orbassano, Turin, 10043, Italy.
Angela J GladingDepartment of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, NY, 14642, USA. angela_glading@urmc.rochester.edu.
Souvik KarInternational Neuroscience Institute, Rudolf-Pichlmayr-Strasse 4, Hannover, 30625, Germany. kar@ini-hannover.de.

Funding

American Heart Association 24POST1191892Deutsche Forschungsgemeinschaft SE2016/10-1ERA-Net NEURON 01EW2306Fondation Leducq 21CVD03 - ReVAMPMinisterio de Ciencia, Innovación y Universidades PID2021-123365OB-I00Ministerio de Ciencia, Innovación y Universidades,Spain SFB958NIH HHS 1HL141131
6 · The paper itself

Abstract

backgroundCerebral cavernous malformations (CCM) are angiographically occult vascular anomalies of the brain, characterized by dilated capillaries, increased vascular permeability, and loss of endothelial junctional protein complexes. Loss-of-function mutations in one of the three genes, namely KRIT1/CCM1, CCM2, and PDCD10/CCM3, have been associated with the disease pathogenesis, although the contribution of other genetic determinants besides CCM genes has been recently identified. Despite recent advances in understanding the molecular mechanism of the disease, the current lack of therapies and its unpredictable clinical behavior represent a significant challenge in the identification of diagnostic biomarkers. ADGRL4/ETLD1 (epidermal growth factor, latrophilin and seven transmembrane domain-containing protein 1), a G-protein coupled receptor (GPCR) protein is a known biomarker of angiogenesis and inflammation, and it has been suggested to be a key therapeutic target for stroke and high-grade gliomas. However, the relevance of ELTD1 in CCM pathogenesis remains unexplored.

methodsThrough different analyses, including whole RNA transcriptome, immunohistochemistry, and real-time PCR, conducted in human CCM patients, cellular and animal models, herein we show the association between CCM disease and ELTD1.

resultsThe whole RNA transcriptome approaches demonstrated ELTD1 is differentially expressed, and gene expression analysis revealed it is significantly upregulated in surgically resected tissue and plasma samples from CCMs, and clinical correlation analysis showed that increased ELTD1 associates with the presence of Focal Neurological Deficits in patients. Immuno-expression showed a strong ELTD1 immunoreactivity in endothelial cells lining affected lesions. According to these elevated levels of ELTD1 in human patients, we also showed a robust increase in the expression level of ELTD1 in cellular and animal models of CCM disease.

conclusionsTaken together, our results demonstrate for the first time ELTD1 involvement in CCM pathogenesis, and its tight link with CCM genes. Thanks to this putative new prognostic biomarker, future clinical studies in larger patient cohorts will aim at improving the CCM disease management and risk stratification in patients, as well as placing the basis for targeted therapeutic strategies in CCM.

Indexed as

Hemangioma, Cavernous, Central Nervous SystemReceptors, G-Protein-CoupledAdultAnimalsBiomarkersFemaleGene Expression ProfilingHumansMaleMiceMiddle AgedPrognosisADGRL4 protein, humanBiomarkersReceptors, G-Protein-CoupledADGRL4/ELTD1AngiogenesisBiomarkersCerebral Cavernous Malformation (CCM)Diagnostic biomarkersPrognostic biomarkersRNA transcriptome

Identifiers

PMID42098603
PMCPMC13321542

What Socratic holds

Textmetadata
LicenceCC BY-NC-ND
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 Socratic graph.