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

Area of Science:

• Genetics
• Neurology
• Molecular Biology

Background:

• Many familial cerebral small vessel disease (CSVD) patients lack identified pathogenic variants in known genes.
• Novel genetic causes for CSVD are needed for improved diagnosis and understanding.

Purpose of the Study:

• To identify novel genes causally linked to familial cerebral small vessel disease (CSVD).

Main Methods:

• Exome data from 258 CSVD patients were analyzed using a gene-based collapsing test for rare protein-truncating variants.
• Functional consequences of variants were assessed via Western blotting and cellular localization studies.
• Clinical and MRI features of affected patients were characterized.

Main Results:

• Truncating variants in LAMB1, escaping nonsense-mediated mRNA decay, were significantly overrepresented in CSVD patients (p < 5x10⁻⁸).
• Truncated LAMB1 protein was expressed and trapped in the cytosol of patient fibroblasts.
• These LAMB1 variants were associated with a novel phenotype combining episodic memory deficits and diffuse vascular leukoencephalopathy.

Conclusions:

• LAMB1 is a novel causal gene for cerebral small vessel disease (CSVD).
• The findings offer crucial insights for CSVD diagnosis, clinical management, and understanding the role of extracellular matrix proteins in neuronal health.