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L1CAM
L1 cell adhesion molecule
The L1CAM gene provides instructions for the L1 cell adhesion molecule, a protein critical for the proper development and function of the nervous system, with variants linked to a spectrum of neurological conditions. The L1CAM gene encodes the L1 cell adhesion molecule (L1 protein), which is essential for neural cell-to-cell adhesion, migration, and the formation of critical neural structures.
L1CAM is located on the long (q) arm of chromosome X, at band Xq28. Arm ratio per GRCh38 - banding schematic.
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Overview
The L1CAM gene, also known as L1 cell adhesion molecule, encodes a protein vital for nervous system development. This protein is found on the surface of neurons and plays a key role in how nerve cells interact and organise. Understanding L1CAM's function is important for comprehending the genetic basis of several inherited neurological conditions, particularly those affecting males due to its X-linked inheritance pattern.
What the gene does
The L1 cell adhesion molecule (L1 protein) is a transmembrane protein that spans the cell membrane of neurons. Its unique positioning allows it to bind to other proteins, including other L1 proteins, on neighbouring neurons, facilitating cell-cell adhesion. This adhesive property is fundamental for the migration and organisation of neurons, as well as the outgrowth of axons, which are crucial for transmitting nerve impulses. The L1 protein also contributes to the formation of the myelin sheath, a protective layer around certain neurons, and the development of synapses, which are junctions where nerve cells communicate. These diverse roles are essential for overall brain development, cognitive abilities, memory, and motor function.
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Chromosome location
The L1CAM gene is located on the X chromosome at position Xq28. This chromosomal location indicates that L1CAM follows an X-linked inheritance pattern, meaning conditions associated with this gene primarily affect males, who have only one X chromosome. Females, with two X chromosomes, are typically carriers.
Protein structure
The L1CAM protein is composed of 1257 amino acids. Its structure includes several key domains and regions crucial for its function. It features six Ig-like C2-type domains, specifically Ig-like C2-type 1 (amino acids 35-125), Ig-like C2-type 2 (amino acids 139-226), Ig-like C2-type 3 (amino acids 240-328), Ig-like C2-type 4 (amino acids 333-420), Ig-like C2-type 5 (amino acids 425-507), and Ig-like C2-type 6 (amino acids 518-607). Additionally, there is a cell attachment site motif (amino acids 554-556) within this region. The protein also contains five Fibronectin type-III domains: Fibronectin type-III 1 (amino acids 615-712), Fibronectin type-III 2 (amino acids 717-810), Fibronectin type-III 3 (amino acids 814-916), Fibronectin type-III 4 (amino acids 920-1015), and Fibronectin type-III 5 (amino acids 1016-1115). Disordered regions are present at amino acids 698-725, 1176-1207, and 1226-1257.
Key variants
Over 350 different genetic changes, or variants, in the L1CAM gene have been identified. These variants can alter the structure or function of the L1 protein, leading to a spectrum of conditions. The specific effect of a variant often depends on its location within the gene and how it impacts protein production or activity.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.1528del | p.Ala510fs | Pathogenic/Likely pathogenic | ★★☆☆ | L1CAM-related disorder |
c.2596_2597del | p.Ile866fs | Pathogenic/Likely pathogenic | ★★☆☆ | X-linked hydrocephalus syndrome |
c.2701C>T | p.Arg901Ter | Pathogenic | ★★☆☆ | Spastic paraplegia |
c.3166+1G>A | - | Pathogenic | ★★☆☆ | L1 syndrome |
c.3496C>T | p.Arg1166Ter | Pathogenic | ★★☆☆ | MASA syndrome |
c.3531-12G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | Spastic paraplegia |
c.3671C>T | p.Ser1224Leu | Pathogenic/Likely pathogenic | ★★☆☆ | Inborn genetic diseases |
c.92-1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | Spastic paraplegia |
c.925G>A | p.Glu309Lys | Pathogenic/Likely pathogenic | ★★☆☆ | Spastic paraplegia |
c.998C>T | p.Pro333Leu | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Variants in the L1CAM gene are primarily associated with L1 syndrome, a group of X-linked neurological disorders that mainly affect males. Individuals with L1 syndrome often experience brain abnormalities, intellectual disability, and difficulties with movement. Rarely, L1CAM variants have also been observed in individuals with both hydrocephalus (fluid build-up in the brain) and Hirschsprung disease, an intestinal disorder characterised by the absence of nerves in parts of the intestine.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic L1CAM variants typically follow x-linked inheritance.
X-linked recessive: sons of a carrier mother have a 50% chance of being affected. Daughters have a 50% chance of being carriers.
UK clinical status
L1CAM is recognised in the UK for its clinical relevance within the NHS Genomic Medicine Service. It is included on several R-code panels for diagnostic testing, such as DDG2P, Familial Hirschsprung Disease, Foetal anomalies (R21), Hereditary spastic paraplegia, Hereditary spastic paraplegia, childhood onset (R61), Hydrocephalus (R86), Intellectual disability, and Paediatric pseudo-obstruction syndrome (R438).
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the L1CAM gene responsible for?
The L1CAM gene provides instructions for making the L1 cell adhesion molecule, a protein essential for the proper development of the nervous system. It helps nerve cells stick together, migrate, and form important connections.
What is L1 syndrome?
L1 syndrome is a group of X-linked neurological conditions caused by variants in the L1CAM gene. It primarily affects males and can lead to brain abnormalities, intellectual disability, and problems with movement.
Why does L1CAM primarily affect males?
L1CAM is located on the X chromosome, meaning it follows an X-linked inheritance pattern. Males have only one X chromosome, so a pathogenic variant on this chromosome will typically result in the condition. Females have two X chromosomes, and usually, the presence of one functional copy prevents them from being affected, although they can be carriers.
References
- Christaller WA, Vos Y, Gebre-Medhin S. L1 syndrome diagnosis complemented with functional analysis of L1CAM variants located to the two N-terminal Ig-like domains. Clinical genetics. 2017. PMID: 26891472
- Ferese R, Zampatti S, Griguoli AM. A New Splicing Mutation in the L1CAM Gene Responsible for X-Linked Hydrocephalus (HSAS). Journal of molecular neuroscience : MN. 2016. PMID: 27207492
- Marín R, Ley-Martos M, Gutiérrez G. Three cases with L1 syndrome and two novel mutations in the L1CAM gene. European journal of pediatrics. 2015. PMID: 25948108
- Weller S, Gärtner J. Genetic and clinical aspects of X-linked hydrocephalus (L1 disease): Mutations in the L1CAM gene. Human mutation. 2001. PMID: 11438988
- Kenwrick S, Watkins A, De Angelis E. Neural cell recognition molecule L1: relating biological complexity to human disease mutations. Human molecular genetics. 2000. PMID: 10767310
- Finckh U, Schröder J, Ressler B. Spectrum and detection rate of L1CAM mutations in isolated and familial cases with clinically suspected L1-disease. American journal of medical genetics. 2000. PMID: 10797421