This report describes LAMB1-related leukoencephalopathy and lissencephaly, a disease of variable severity and phenotypes. The most severe types exhibit autosomal recessive inheritance, however, late-onset memory dysfunction has been observed in heterozygous individuals; severity typically correlates inversely with age of onset. A severe type, designated lissencephaly 5, is described in OMIM (MIM:615191).
The LAMB1 gene encodes a component of laminin; one of its many functions is in the organization of the laminar architecture of the cerebral cortex. There is a single orthologous gene in Drosophila, LanB1, for which multiple genetic reagents have been generated, including classical loss-of-function mutations, RNAi-targeting constructs, and overexpression constructs. Dmel\LanB1 is also orthologous to the human genes LAMB2, LAMB3, and LAMB4.
Multiple UAS constructs of human Hsap\LAMB1 have been introduced into flies, including wild-type and variants implicated in this disease; see the 'Disease-Implicated Variants' table below. The wild-type human gene fails to rescue Dmel\LanB1 loss-of-function phenotypes. The Hsap\LAMB1 variants have been assessed for gain-of-function phenotypes.
Animals homozygous for loss-of-function mutations of Dmel\LanB1 typically die during embryogenesis or early larval stages. In the context of this disease model, the role of LanB1 in the brain has been studied. LanB1 mutations analogous to human disease-implicated variants have been characterized; these are also shown in the 'Disease-Implicated Variants' table below.
[updated Jun. 2025 by FlyBase; FBrf0222196]
A wide clinical spectrum of LAMB1-related leukoencephalopathy has been described thus far including lissencephaly 5 (MIM:615191) characterized by cobblestone changes in the cortex, congenital hydrocephalus, seizures and severe developmental delay; infantile- to childhood-onset cases with seizures, macrocephaly, and brain malformation; and adult-onset cases presenting with gait disturbance, cognitive decline, and diffuse white matter lesions (Yasuda et al., 2025; pubmed:40237576; FBrf0262420).
LAMB1-related leukoencephalopathy is a very rare monogenetic neurological disease caused by pathogenic variants in the LAMB1 gene. In more severe disease, autosomal recessive inheritance is observed; late-onset memory dysfunction has been observed in heterozygous individuals (Yasuda et al., 2025; pubmed:40237576; FBrf0262420).
LAMB1 encodes a component of laminin, a family of extracellular matrix glycoproteins. Binding to cells via a high affinity receptor, laminin is thought to mediate the attachment, migration and organization of cells into tissues during embryonic development by interacting with other extracellular matrix components. Laminins are involved in the organization of the laminar architecture of the cerebral cortex. [GeneCards, LAMB1; 2025.06.17]
Many to one: multiple human genes to 1 Drosophila gene.
High-scoring ortholog of human LAMB1 and LAMB2; low- to moderate-scoring ortholog of LAMB3 and LAMB4 (1 Drosophila to multiple human).
