Academic Journal
End-Truncated LAMB1 Causes a Hippocampal Memory Defect and a Leukoencephalopathy.
| العنوان: | End-Truncated LAMB1 Causes a Hippocampal Memory Defect and a Leukoencephalopathy. |
|---|---|
| المؤلفون: | Aloui, Chaker, Hervé, Dominique, Marenne, Gaelle, Savenier, Florian, Le Guennec, Kilan, Bergametti, Francoise, Verdura, Edgard, Ludwig, Thomas, Lebenberg, Jessica, Jabeur, Waliyde, Morel, Hélène, Coste, Thibault, Demarquay, Geneviève, Bachoumas, Panagiotis, Cogez, Julien, Mathey, Guillaume, Bernard, Emilien, Consortium, Frex, Chabriat, Hugues, Génin, Emmanuelle, Tournier-Lasserve, Elisabeth |
| المساهمون: | Maladies neurodéveloppementales et neurovasculaires (NeuroDiderot (UMR_S_1141 / U1141)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal Paris, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), 2Service de Génétique Moléculaire Neurovasculaire, Groupe hospitalier Saint-Louis - Lariboisière - Fernand Widal AP-HP, Paris, France, Hospices Civils de Lyon (HCL), Service de Neurologie CHPC - Site Louis Pasteur, Site Louis Pasteur CHPC, CH Centre Hospitalier Public du Cotentin (CHPC)-CH Centre Hospitalier Public du Cotentin (CHPC), Service de Neurologie CHU Caen, Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Service de neurologie CHRU Nancy, Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Hôpital neurologique et neurochirurgical Pierre Wertheimer CHU - HCL, Institut NeuroMyoGène (INMG), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), ANR-16-RHUS-0004,TRT-cSVD,TRT-cSVD(2016) |
| المصدر: | ISSN: 0364-5134. |
| بيانات النشر: | CCSD Wiley |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | MESH: Adult, MESH: Aged, MESH: Male, MESH: Memory Disorders, MESH: Middle Aged, MESH: Phenotype, MESH: Registries, MESH: Cerebral Small Vessel Diseases, MESH: Exome, MESH: Female, MESH: Hippocampus, MESH: Humans, MESH: Laminin, MESH: Leukoencephalopathies, MESH: Magnetic Resonance Imaging, [SDV]Life Sciences [q-bio], [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] |
| الوصف: | International audience ; ObjectiveThe 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.MethodsWe 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.ResultsWe 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.InterpretationThese 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. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| Relation: | info:eu-repo/semantics/altIdentifier/pmid/34606115; PUBMED: 34606115 |
| DOI: | 10.1002/ana.26242 |
| الاتاحة: | https://hal.science/hal-03618954 https://doi.org/10.1002/ana.26242 |
| رقم الانضمام: | edsbas.745F2297 |
| قاعدة البيانات: | BASE |
كن أول من يترك تعليقا!