Functional study of pathogenic variants in LAMB1 using Drosophila provides new insights

Rare variants in LAMB1 are associated with a variety of neurodevelopmental and neurodegenerative phenotypes in human. However, their genotype-phenotype relationship was unknown. Using Drosophila and cultured human cells, we provide functional evidence that some disease-associated variants behave as loss-of-function alleles whereas others have gain-of-function properties. We also show that the fly ortholog of LAMB1 is expressed exclusively in glia cells in Drosophila brain, providing novel insights into pathogenic mechanisms.