End-Truncated LAMB1 Causes a Hippocampal Memory Defect and a Leukoencephalopathy
Chaker Aloui PhD
Université de Paris, INSERM UMR 1141 NeuroDiderot, Paris, France
Search for more papers by this authorDominique Hervé MD
Université de Paris, INSERM UMR 1141 NeuroDiderot, Paris, France
AP-HP, Groupe Hospitalier Saint-Louis Lariboisière-Fernand-Widal, Service de Neurologie, Centre de Référence des Maladies Vasculaires Rares du Cerveau et de l'Œil (CERVCO), Paris, France
These authors contributed equally to this work.
Search for more papers by this authorGaelle Marenne PhD
Université de Brest, Inserm, EFS, CHU Brest, UMR 1078, GGB, Brest, France
These authors contributed equally to this work.
Search for more papers by this authorFlorian Savenier MD
Université de Paris, INSERM UMR 1141 NeuroDiderot, Paris, France
These authors contributed equally to this work.
Search for more papers by this authorKilan Le Guennec PhD
Université de Paris, INSERM UMR 1141 NeuroDiderot, Paris, France
These authors contributed equally to this work.
Search for more papers by this authorFrancoise Bergametti PhD
Université de Paris, INSERM UMR 1141 NeuroDiderot, Paris, France
These authors contributed equally to this work.
Search for more papers by this authorEdgard Verdura PhD
Université de Paris, INSERM UMR 1141 NeuroDiderot, Paris, France
Search for more papers by this authorThomas E. Ludwig PhD
Université de Brest, Inserm, EFS, CHU Brest, UMR 1078, GGB, Brest, France
Search for more papers by this authorJessica Lebenberg PhD
Université de Paris, INSERM UMR 1141 NeuroDiderot, Paris, France
Search for more papers by this authorWaliyde Jabeur MD
Université de Paris, INSERM UMR 1141 NeuroDiderot, Paris, France
Search for more papers by this authorHélène Morel PharmD
Université de Paris, INSERM UMR 1141 NeuroDiderot, Paris, France
AP-HP, Service de Génétique Moléculaire Neurovasculaire, Hôpital Saint-Louis, Paris, France
Search for more papers by this authorThibault Coste PharmD
Université de Paris, INSERM UMR 1141 NeuroDiderot, Paris, France
AP-HP, Service de Génétique Moléculaire Neurovasculaire, Hôpital Saint-Louis, Paris, France
Search for more papers by this authorGeneviève Demarquay MD
Hôpital Neurologique, Hospices Civils de Lyon, Lyon Neuroscience Research Center (CRNL), Brain Dynamics and Cognition Team (Dycog), INSERM U1028, CNRS UMR5292, Lyon, France
Search for more papers by this authorPanagiotis Bachoumas MD
Centre Hospitalier Public Du Cotentin, Cherbourg-en-Cotentin, France
Search for more papers by this authorJulien Cogez MD
CHU Caen, Department of Neurology, CHU de Caen Côte de Nacre, Caen, France
Search for more papers by this authorGuillaume Mathey MD
Neurology Unit, University Hospital of Nancy, Nancy, France
Search for more papers by this authorEmilien Bernard MD
Department of Neurology, Hôpital Neurologique Pierre Wertheimer, Hospices Civils de Lyon, Bron, France
Institut NeuroMyoGène, INSERM-CNRS-UMR, Université Claude Bernard, Lyon, France
Search for more papers by this authorFREX consortium
Search for more papers by this authorHugues Chabriat MD, PhD
Université de Paris, INSERM UMR 1141 NeuroDiderot, Paris, France
AP-HP, Groupe Hospitalier Saint-Louis Lariboisière-Fernand-Widal, Service de Neurologie, Centre de Référence des Maladies Vasculaires Rares du Cerveau et de l'Œil (CERVCO), Paris, France
Search for more papers by this authorEmmanuelle Génin PhD
Université de Brest, Inserm, EFS, CHU Brest, UMR 1078, GGB, Brest, France
Search for more papers by this authorCorresponding Author
Elisabeth Tournier-Lasserve MD
Université de Paris, INSERM UMR 1141 NeuroDiderot, Paris, France
AP-HP, Service de Génétique Moléculaire Neurovasculaire, Hôpital Saint-Louis, Paris, France
Address correspondence to Dr Tournier-Lasserve, INSERM UMR 1141, 48 Boulevard Sérurier, 75019 Paris, France. E-mail: [email protected]
Search for more papers by this authorChaker Aloui PhD
Université de Paris, INSERM UMR 1141 NeuroDiderot, Paris, France
Search for more papers by this authorDominique Hervé MD
Université de Paris, INSERM UMR 1141 NeuroDiderot, Paris, France
AP-HP, Groupe Hospitalier Saint-Louis Lariboisière-Fernand-Widal, Service de Neurologie, Centre de Référence des Maladies Vasculaires Rares du Cerveau et de l'Œil (CERVCO), Paris, France
These authors contributed equally to this work.
Search for more papers by this authorGaelle Marenne PhD
Université de Brest, Inserm, EFS, CHU Brest, UMR 1078, GGB, Brest, France
These authors contributed equally to this work.
Search for more papers by this authorFlorian Savenier MD
Université de Paris, INSERM UMR 1141 NeuroDiderot, Paris, France
These authors contributed equally to this work.
Search for more papers by this authorKilan Le Guennec PhD
Université de Paris, INSERM UMR 1141 NeuroDiderot, Paris, France
These authors contributed equally to this work.
Search for more papers by this authorFrancoise Bergametti PhD
Université de Paris, INSERM UMR 1141 NeuroDiderot, Paris, France
These authors contributed equally to this work.
Search for more papers by this authorEdgard Verdura PhD
Université de Paris, INSERM UMR 1141 NeuroDiderot, Paris, France
Search for more papers by this authorThomas E. Ludwig PhD
Université de Brest, Inserm, EFS, CHU Brest, UMR 1078, GGB, Brest, France
Search for more papers by this authorJessica Lebenberg PhD
Université de Paris, INSERM UMR 1141 NeuroDiderot, Paris, France
Search for more papers by this authorWaliyde Jabeur MD
Université de Paris, INSERM UMR 1141 NeuroDiderot, Paris, France
Search for more papers by this authorHélène Morel PharmD
Université de Paris, INSERM UMR 1141 NeuroDiderot, Paris, France
AP-HP, Service de Génétique Moléculaire Neurovasculaire, Hôpital Saint-Louis, Paris, France
Search for more papers by this authorThibault Coste PharmD
Université de Paris, INSERM UMR 1141 NeuroDiderot, Paris, France
AP-HP, Service de Génétique Moléculaire Neurovasculaire, Hôpital Saint-Louis, Paris, France
Search for more papers by this authorGeneviève Demarquay MD
Hôpital Neurologique, Hospices Civils de Lyon, Lyon Neuroscience Research Center (CRNL), Brain Dynamics and Cognition Team (Dycog), INSERM U1028, CNRS UMR5292, Lyon, France
Search for more papers by this authorPanagiotis Bachoumas MD
Centre Hospitalier Public Du Cotentin, Cherbourg-en-Cotentin, France
Search for more papers by this authorJulien Cogez MD
CHU Caen, Department of Neurology, CHU de Caen Côte de Nacre, Caen, France
Search for more papers by this authorGuillaume Mathey MD
Neurology Unit, University Hospital of Nancy, Nancy, France
Search for more papers by this authorEmilien Bernard MD
Department of Neurology, Hôpital Neurologique Pierre Wertheimer, Hospices Civils de Lyon, Bron, France
Institut NeuroMyoGène, INSERM-CNRS-UMR, Université Claude Bernard, Lyon, France
Search for more papers by this authorFREX consortium
Search for more papers by this authorHugues Chabriat MD, PhD
Université de Paris, INSERM UMR 1141 NeuroDiderot, Paris, France
AP-HP, Groupe Hospitalier Saint-Louis Lariboisière-Fernand-Widal, Service de Neurologie, Centre de Référence des Maladies Vasculaires Rares du Cerveau et de l'Œil (CERVCO), Paris, France
Search for more papers by this authorEmmanuelle Génin PhD
Université de Brest, Inserm, EFS, CHU Brest, UMR 1078, GGB, Brest, France
Search for more papers by this authorCorresponding Author
Elisabeth Tournier-Lasserve MD
Université de Paris, INSERM UMR 1141 NeuroDiderot, Paris, France
AP-HP, Service de Génétique Moléculaire Neurovasculaire, Hôpital Saint-Louis, Paris, France
Address correspondence to Dr Tournier-Lasserve, INSERM UMR 1141, 48 Boulevard Sérurier, 75019 Paris, France. E-mail: [email protected]
Search for more papers by this authorAbstract
Objective
The majority of patients with a familial cerebral small vessel disease (CSVD) referred for molecular screening do not show pathogenic variants in known genes. In this study, we aimed to identify novel CSVD causal genes.
Methods
We performed a gene-based collapsing test of rare protein-truncating variants identified in exome data of 258 unrelated CSVD patients of an ethnically matched control cohort and of 2 publicly available large-scale databases, gnomAD and TOPMed. Western blotting was used to investigate the functional consequences of variants. Clinical and magnetic resonance imaging features of mutated patients were characterized.
Results
We showed that LAMB1 truncating variants escaping nonsense-mediated messenger RNA decay are strongly overrepresented in CSVD patients, reaching genome-wide significance (p < 5 × 10−8). Using 2 antibodies recognizing the N- and C-terminal parts of LAMB1, we showed that truncated forms of LAMB1 are expressed in the endogenous fibroblasts of patients and trapped in the cytosol. These variants are associated with a novel phenotype characterized by the association of a hippocampal type episodic memory defect and a diffuse vascular leukoencephalopathy.
Interpretation
These findings are important for diagnosis and clinical care, to avoid unnecessary and sometimes invasive investigations, and also from a mechanistic point of view to understand the role of extracellular matrix proteins in neuronal homeostasis. ANN NEUROL 2021;90:962–975
Potential Conflicts of Interests
Nothing to report.
Supporting Information
| Filename | Description |
|---|---|
| ana26242-sup-0001-TableS1.docxWord 2007 document , 12.9 KB | Table S1. Gene-based burden test (Fisher exact) of rare High-Impact and missense damaging variants between CSVD patients (n = 207) and FREX controls (n = 566). Missense damaging variants included possibly and probably damaging predicted by PolyPhen V2.2.2 |
| ana26242-sup-0002-TableS2.xlsxExcel 2007 spreadsheet , 170.8 KB | Table S2. Gene based burden test comparing all rare PTV carriers for the top 7 genes in CSVD versus gnomAD v3 and TOPMed Freeze5 |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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