| Full gene name: | L1 cell adhesion molecule |
|---|---|
| Entrez Gene ID: | 3897 |
| Location: | Xq28 |
| Synonyms: | SPG1, CD171, NCAM-L1, MASA, MIC5, S10, CAML1, HSAS1, N-CAM-L1, N-CAML1, HSAS |
| Type: | protein-coding |
SNPs given by the user that are near or inside this gene:
| SNP | Distance (bp) | Direction |
|---|---|---|
| rs3020789 | 233984 | downstream |
The protein encoded by this gene is an axonal glycoprotein belonging to the immunoglobulin supergene family. The ectodomain, consisting of several immunoglobulin-like domains and fibronectin-like repeats (type III), is linked via a single transmembrane sequence to a conserved cytoplasmic domain. This cell adhesion molecule plays an important role in nervous system development, including neuronal migration and differentiation. Mutations in the gene cause three X-linked neurological syndromes known by the acronym CRASH (corpus callosum hypoplasia, retardation, aphasia, spastic paraplegia and hydrocephalus). Alternative splicing of a neuron-specific exon is thought to be functionally relevant. [provided by RefSeq, Jul 2008]
| OMIM ID: | `OMIM ID 308840 `_ |
|---|
Allelic Variants (Selected Examples)
.0001 HYDROCEPHALUS, X-LINKED
The mutation in the L1CAM gene identified by Rosenthal et al. (1992) in affected members and carriers in 1 family with X-linked hydrocephalus (307000) was an A-to-C transversion at position -19 in a putative branchpoint sequence of the L1CAM gene. The mutation resulted in aberrant splicing with deletion of exon Q and insertion of 69 additional basepairs.
.0002 HYDROCEPHALUS, X-LINKED
In a patient with severe X-linked hydrocephalus (307000), Jouet et al. (1993) observed a G-to-A transition at nucleotide 791 of the cDNA sequence, resulting in a cys264-to-tyr substitution in the third immunoglobulin type C2 domain of the mature protein. The mutation would eliminate the potential for disulfide bridge formation and have a profound effect on L1 secondary structure. From analogy to NCAM (116930) and from the conservation of cys264 in analogous proteins of rat, mouse, chicken, and Drosophila, one can conclude that the mutation was probably disruptive. Furthermore, an RsaI site created by the mutation segregated fully with the disease in the extended pedigree and did not correspond to a common polymorphism.
.0003 HYDROCEPHALUS, X-LINKED
Van Camp et al. (1993) screened 25 X-linked hydrocephalus (307000) families for mutations. The mutation reported by Rosenthal et al. (1992) was found in none of them. One family, however, showed a 1.3-kb genomic duplication in the 3-prime region of L1CAM. The 1.3-kb duplication comprised the 3-prime end of the L1CAM open reading frame, part of the upstream intron, and 756 bp of 3-prime untranslated sequence. Van Camp et al. (1993) showed that the duplication gives rise to aberrant splicing of L1CAM mRNA and that translation of the new mRNA replaces the 35 carboxy-terminal amino acids of the L1CAM protein with a new 75-amino acid sequence.
.0004 MASA SYNDROME
In an affected member of a family with the MASA syndrome (303350), Jouet et al. (1994) observed a C-to-G transversion at nucleotide 630 converting his to gln at amino acid residue 210. The change occurred in exon 6 and produced a change in the protein in the second immunoglobulin domain of L1. All 5 affected members of the family had agenesis of the corpus callosum, and 1 of these also presented with marked hydrocephalus.
.0005 MASA SYNDROME
In the course of L1CAM mutation analysis in 8 unrelated patients with MASA syndrome (303350), Vits et al. (1994) found 3 different L1CAM mutations: a deletion removing part of the open reading frame and 2 point mutations resulting in amino acid substitutions. The 2 missense mutations were asp598 to asn (D598N) in the sixth immunoglobulin domain of the protein; and his210 to gln (H210Q) (308840.0004) in the second immunoglobulin domain.
.0006 HYDROCEPHALUS, X-LINKED
In a family with a history of hydrocephalus (307000), Jouet et al. (1994) found a G-to-A mutation in exon 11 of the L1CAM gene that caused a gly-to-arg substitution at residue 452.
.0007 HYDROCEPHALUS, X-LINKED
In the original hydrocephalus (307000) family described by Bickers and Adams (1949) and further characterized by Edwards et al. (1961), Jouet et al. (1994) used SSCP to detect a G-to-A change in exon 6 that substituted gln for arg at residue 184.
.0008 MASA SYNDROME
In a family reported by Kenwrick et al. (1986) as having spastic paraplegia-1, but later determined to have MASA syndrome (303350), Jouet et al. (1994) found a 2-bp deletion in exon 26 which resulted in a shift of the reading frame and the introduction of a premature stop codon 19 nucleotides downstream. This change predicts a truncated protein in which 95 of the 115 highly conserved amino acids are replaced by 7 novel residues.
.0009 HYDROCEPHALUS, X-LINKED
Fransen et al. (1994) reported a family in which 2 males, an uncle and a nephew, had typical symptoms of MASA syndrome, and a third male, a maternal first cousin of the uncle, was born hydrocephalic (307000) and died at the age of 15 years in an institution for the mentally handicapped. At that time, he had extreme macrocephaly, severe spasticity, and mental retardation. The same L1CAM mutation was found in all 3 cases. A C-to-T transition in exon 28 at position 3581 of the L1CAM cDNA sequence caused a ser1194-to-leu substitution in the cytoplasmic domain of the L1CAM molecule.
.0010 CRASH SYNDROME
In a family reported by Fryns et al. (1991) in which various members displayed features characteristic of complicated spastic paraplegia (182600), MASA syndrome (303350), or X-linked hydrocephalus due to aqueduct stenosis (307000), Ruiz et al. (1995) found an I179S mutation in the L1CAM gene.
.0011 CRASH SYNDROME
In a large family described by Kaepernick et al. (1994) in which different members displayed features consistent with one or another of the 3 L1CAM-associated syndromes, spastic paraplegia type 1 (312900), MASA syndrome (303350), or X-linked hydrocephalus (307000), Ruiz et al. (1995) identified a G370R mutation in the L1CAM gene in all affected members.
.0012 HYDROCEPHALUS, X-LINKED, WITH HIRSCHSPRUNG DISEASE
In a child with features of X-linked hydrocephalus (307000) who also had Hirschsprung disease and cleft palate, Okamoto et al. (1997) identified a 2-bp deletion of exon 18 in the L1CAM gene, resulting in a frameshift and premature termination was found. The mother was heterozygous for this mutation. Okamoto et al. (1997) acknowledged that X-linked hydrocephalus and Hirschsprung disease may be independent events in this patient, but suggested that L1CAM may contribute to both phenotypes.
.0013 HYDROCEPHALUS, X-LINKED
In a family with X-linked hydrocephalus (307000), Du et al. (1998) identified a C-to-T transition at position 924 in exon 8 of the L1CAM gene. This was predicted to have no effect on protein structure, as it affected the third position of a glycine codon (G308G). However, the C-to-T transition created a potential 5-prime splice site consensus sequence resulting in an in-frame 69-bp deletion from exon 8 with a consequent 23 amino acid deletion. RT-PCR of RNA from an affected male fetus confirmed the use of the new splice site.
.0014 HYDROCEPHALUS, X-LINKED, WITH HIRSCHSPRUNG DISEASE
Parisi et al. (2002) described a male infant who had severe hydrocephalus (307000) identified in the prenatal period with evidence of aqueductal stenosis and adducted thumbs at birth. He developed chronic constipation, and rectal biopsy confirmed the diagnosis of Hirschsprung disease. Molecular testing of the L1CAM gene demonstrated a 2254G-A mutation, resulting in a val752-to-met amino acid substitution (V752M). A common polymorphism in RET, but no mutation, was identified. Parisi et al. (2002) stated that this patient represented the third example of coincident hydrocephalus and Hirschsprung disease in an individual with an identified L1CAM mutation. They hypothesized that L1CAM-mediated cell adhesion may be important for the ability of ganglion cell precursors to populate the gut, and that L1CAM may modify the effects of a Hirschsprung disease-associated gene to cause intestinal aganglionosis.
.0015 HYDROCEPHALUS, X-LINKED, WITH HIRSCHSPRUNG DISEASE
In 2 brothers with hydrocephalus (307000) and Hirschsprung disease, Okamoto et al. (2004) identified a G-to-A transition at position +5 of the donor splice site of intron 15 of the L1CAM gene (IVS15+5G-A). Bilateral adducted thumbs and flexion contracture of the fingers were noted. The mother was heterozygous for the mutation; male first cousins and a maternal uncle of hers had X-linked hydrocephalus only.
.0016 HYDROCEPHALUS, X-LINKED, WITH CONGENITAL IDIOPATHIC INTESTINAL PSEUDOOBSTRUCTION
Bott et al. (2004) described an association between hydrocephalus due to stenosis of the aqueduct of Sylvius (307000) and a form of congenital idiopathic intestinal pseudoobstruction (see 300048) in which Cajal cells were lacking in an infant in whom they identified a 2920G-T transversion in exon 22 of the L1CAM gene, resulting in a gln974-to-ter (Q974X) substitution. The mother was a carrier. A maternal great uncle had mental retardation and died during childhood. By fetal ultrasonography, the patient was found at 32 weeks’ gestation to have hydrocephalus and was born prematurely at 34 weeks’ gestation as a result of maternal eclampsia. At birth, bilateral adducted thumbs, bilateral nystagmus, convergent strabismus, spastic paraplegia, and abdominal distention were noted. The patient’s mother and grandmother had had several spontaneous abortions. Bott et al. (2004) noted that Cajal cells are the pacemaker cells of the gut. They generate the physiologic slow waves in the intestinal tract that are responsible for autonomic gastrointestinal motility (Jain et al., 2003). The KIT oncogene (164920) encodes a protein responsible for the development of Cajal cells. Bott et al. (2004) suggested that the selective expression of L1CAM in the gut or kidney may explain the association of HSAS with hydronephrosis and with hydroureter or Hirschsprung disease.
.0017 HYDROCEPHALUS, X-LINKED
In 4 affected males from a family with X-linked hydrocephalus (307000), Gu et al. (1996) identified a 719C-T transition in exon 7 of the L1CAM gene, resulting in a pro240-to-leu (P240L) substitution in the third highly conserved Ig-like domain. Three of the older patients had died between 5 and 8 months of age; the proband had adducted thumbs, short stature, severe mental retardation, and spasticity.
Basel-Vanagaite et al. (2006) identified the P240L mutation in 2 male sibs with X-linked partial agenesis of the corpus callosum (304100) and mild mental retardation. Neither sib had hydrocephalus, adducted thumbs, or absent speech. The older sib also had Hirschsprung disease and congenital dislocation of the radial heads bilaterally, resulting in limited extension and supination of the elbows. Basel-Vanagaite et al. (2006) emphasized the well-known inter- and intrafamilial phenotypic variability in patients with L1CAM mutations.
.0018 HYDROCEPHALUS, X-LINKED
In a Swedish boy with X-linked hydrocephalus, cognitive delay, and adducted thumbs (307000), Rehnberg et al. (2011) identified a hemizygous G-to-C transversion in intron 26 of the L1CAM gene (c.3458-1G-C), predicted to result in the deletion of exon 26 and a frameshift in exons 27 and 28. This would likely cause a loss of function of most of the cytoplasmic domain of the protein, which is a multifunctional region required for the initial protrusion of axons from the neuronal soma. Rehnberg et al. (2011) suggested that the mutation would disrupt cytoskeletal interactions. Family history was notable for 2 deceased maternal uncles with hydrocephalus, cognitive impairment, spastic paraplegia, and adducted thumbs. The mutation was also found in 3 female relatives of the proband, including his unaffected mother, maternal grandmother, and sister. Rehnberg et al. (2011) noted that the mother developed metastatic clear cell renal cell carcinoma (RCC; 144700) at age 46, and they speculated that the L1CAM mutation may have stimulated tumor migration and growth in this patient.
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