This report describes L1 syndrome, a spectrum of X-linked recessive conditions caused by mutation in the L1CAM gene (see MIM:308840, MIM:307000, MIM:303350, MIM:304100). L1CAM encodes a neural cell adhesion molecule that plays multiple roles during neural development. There is a single orthologous gene in Drosophila, Nrg (neuroglian), for which classical amorphic and hypomorphic mutations, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated. Dmel\Nrg is also orthologous to several related human genes that encode cell adhesion molecules, NRCAM, CHL1, and NFASC.
Multiple UAS constructs of the human Hsap\L1CAM gene have been introduced into flies, including wild-type and variants associated with human disease. Heterologous rescue (functional complementation) has been demonstrated for the neuroanatomy and neurophysiology phenotypes of a Dmel\Nrg missense mutation. Variant(s) implicated in human disease tested (as transgenic human gene, L1CAM): the H210Q, E309K, Y1070C, C264Y, R184Q, L120V, and I291T variant forms of the human gene have been introduced into flies and assessed for ability to rescue Nrg mutant phenotypes. Different L1CAM mutations have been found to have distinct effects on axon guidance and synapse formation. These variants have been associated with specific forms of L1 syndrome: H210Q and E309K with MASA syndrome; C264Y and R184Q with X-linked hydrocephalus; Y1070C, C264Y, L120V, R184Q, and I291T with HSAS.
Animals homozygous for amorphic mutations of Dmel\Nrg die during embryonic or early larval stages. Animals carrying a number of hypomorphic mutations survive to adulthood, but exhibit neuroanatomy defects, including of synaptic terminals, and behavioral defects. Multiple physical and genetic interactions have been described for Dmel\Nrg; see below and in the Nrg gene report.
[updated Aug. 2018 by FlyBase; FBrf0222196]
[MASA SYNDROME](https://omim.org/entry/303350)
[L1 CELL ADHESION MOLECULE; L1CAM](https://omim.org/entry/308840)
L1 syndrome describes a group of conditions that primarily affect the nervous system and occur almost exclusively in males. These conditions vary in severity and include, from most severe to least, X-linked hydrocephalus with stenosis of the aqueduct of Sylvius (HSAS), MASA syndrome, spastic paraplegia type 1, and X-linked complicated corpus callosum agenesis. Severely affected individuals may survive only a short time after birth, while those with mild features live into adulthood. Family members with L1 syndrome caused by the same mutation may have different forms of the condition. [Genetics Home Reference, L1 syndrome; 2018.08.20]
L1 syndrome is mainly characterized by hydrocephalus (increased fluid in the center of the brain), spasticity of the lower limbs (muscle stiffness), adducted thumbs (clasped towards the palm), aphasia (difficulty with speaking), seizures, and agenesis of the corpus callosum (underdeveloped or absent connecting tissue between the left and right hemispheres of the brain). Affected individuals have intellectual disability in the mild to moderate range. [NORD, L1 Syndrome; 2018.08.20]
L1 syndrome is caused by mutations in the L1CAM gene, which affect about 1 in 30,000 males. [NORD, L1 Syndrome; 2018.08.20]
L1 syndrome is an inherited, X-linked disorder caused by mutations in the L1CAM gene. [Genetics Home Reference, L1 syndrome; 2018.08.20]
L1CAM encodes a glycoprotein that belongs to the immunoglobulin supergene family and acts as a neural cell adhesion molecule involved in the dynamics of cell adhesion and in the generation of transmembrane signals. During brain development, it is critical in multiple processes, including neuronal migration, axonal growth and fasciculation, and synaptogenesis; in the mature brain, it plays a role in the dynamics of neuronal structure and function, including synaptic plasticity. [Gene Cards, L1CAM; 2018.08.20]
Many to one: 4 human to 1 Drosophila. The other human genes are NRCAM, CHL1, and NFASC.
Moderate- to high-scoring ortholog of human NRCAM, CHL1, L1CAM, and NFASC (1 Drosophila to 4 human). Dmel\Nrg shares 29% identity and 47% similarity with the L1CAM gene.
