End-Truncated LAMB1 Causes a Hippocampal Memory Defect and a Leukoencephalopathy

Ann Neurol. 2021 Dec;90(6):962-975. doi: 10.1002/ana.26242. Epub 2021 Oct 20.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Cerebral Small Vessel Diseases / diagnostic imaging
  • Cerebral Small Vessel Diseases / genetics*
  • Exome
  • Female
  • Hippocampus / diagnostic imaging*
  • Humans
  • Laminin / genetics*
  • Leukoencephalopathies / diagnostic imaging
  • Leukoencephalopathies / genetics*
  • Magnetic Resonance Imaging
  • Male
  • Memory Disorders / diagnostic imaging
  • Memory Disorders / genetics*
  • Middle Aged
  • Phenotype
  • Registries


  • LAMB1 protein, human
  • Laminin