Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0025362 (mental retardation)
 15,878 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The murine and human genes for the L1 neural adhesion molecule were shown to lie on conserved regions of the X chromosome to which genes responsible for several neuromuscular diseases have been mapped and which are adjacent to the fragile site (FRAXA) associated with mental retardation. By pulsed-field gel mapping we have demonstrated physical linkage between the L1 gene and other genes located in Xq28: L1 lies between the eye pigment RCP, GCP locus and the glucose-6-phosphate dehydrogenase (G6PD) gene. This location is compatible with the implication of the L1 molecule in one of the X-linked neuromuscular diseases mapped to this region.
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PMID:The gene encoding L1, a neural adhesion molecule of the immunoglobulin family, is located on the X chromosome in mouse and man. 238 85

L1 is a neuronal cell adhesion molecule with important functions in the development of the nervous system. The gene encoding L1 is located near the telomere of the long arm of the X chromosome in Xq28. We review here the evidence that several X-linked mental retardation syndromes including X-linked hydrocephalus (HSAS), MASA syndrome, X-linked complicated spastic paraparesis (SP1) and X-linked corpus callosum agenesis (ACC) are all due to mutations in the L1 gene. The inter- and intrafamilial variability in families with an L1 mutation is very wide, and patients with HSAS, MASA, SP1 and ACC can be present within the same family. Therefore, we propose here to refer to this clinical syndrome with the acronym CRASH, for Corpus callosum hypoplasia, Retardation, Adducted thumbs, Spastic paraplegia and Hydrocephalus.
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PMID:CRASH syndrome: clinical spectrum of corpus callosum hypoplasia, retardation, adducted thumbs, spastic paraparesis and hydrocephalus due to mutations in one single gene, L1. 855 2

The cell adhesion molecule L1 plays an important role in neural development. We have previously demonstrated that the second immunoglobulin-like domain (Ig2) of L1 contains both homophilic binding and neuritogenic activities (Zhao, X., and Siu, C.-H. (1995) J. Biol. Chem. 270, 29413-29421). Recently, two mutations (R184Q and H210Q) within the Ig2 region of the human L1 gene have been shown to be responsible for X-linked hydrocephalus and the related MASA (mental retardation, aphasia, shuffling gait, and adducted thumbs) syndrome. Glutathione S-transferase-Ig2 fusion proteins containing these mutations were used to evaluate their effects on L1. The homophilic binding activity of fusion proteins and their ability to promote neurite outgrowth from retinal cells were examined. The R184Q mutation led to a complete loss of both homophilic binding and neuritogenic activities, while the H210Q mutation resulted only in a partial loss. These results provide, for the first time, direct demonstration of the deleterious effects of hydrocephalus/MASA mutations on two intrinsic properties of L1.
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PMID:Differential effects of two hydrocephalus/MASA syndrome-related mutations on the homophilic binding and neuritogenic activities of the cell adhesion molecule L1. 863 66

Familial spastic paraplegia (FSP or SPG) is a genetically heterogeneous group of upper motor neuron syndromes. To date, two distinct loci for X-linked recessive type (SPG1 and SPG2), three loci for autosomal dominant type (FSP1, FSP2 and FSP3), and one locus for autosomal recessive type have been reported. SPG1 and SPG2 have been mapped to Xq28 and Xq21-q22, respectively. SPG1 shows a mutation in the gene for neural cell adhesion molecule L1 (LICAM), which is an axonal glycoprotein involved in neuronal migration and differentiation. Different mutations of the same L1 gene also cause. MASA (mental retardation, aphasia, spastic paraplegia, adducted thumbs) syndrome and X-linked hydrocephalus. SPG2 shows mutations in one of the major myelin proteins, the proteolipid protein (PLP) gene, and is allelic to Pelizaeus-Merzbacher disease. Thus, mutations in two functionally distinct genes manifest the phenotype of X-linked spastic paraparesis. Three dominantly inherited spastic paraplegia genes have been genetically mapped to regions of chromosomes, yet no specific genes or mutations have been identified. FSP1 is mapped to a region of 7 cM on chromosome 14q12-q23 (approximately 20% of dominant FSP families) and FSP2 to 4 cM on chromosome 2p21-p24 (approximately 70% of dominant FSP families). Anticipation (increasing clinical severity in successive generations) has been observed in both FSP1 and FSP2 families. Another autosomal dominant FSP (FSP3) has been mapped in the centromeric region of chromosome 15q (< 10% of dominant FSP families). An autosomal recessive FSP has been mapped to chromosome 8q. The definite genetic heterogeneity in FSP indicates that a multitude of genes/proteins can cause spastic paraplegia. Clinical features of each of the loci which may permit differential diagnosis are discussed. We also present pedigrees of two new FSP families.
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PMID:Molecular genetics of familial spastic paraplegia: a multitude of responsible genes. 878 67

The neuronal cell adhesion molecule L1 (L1CAM) is a transmembrane glycoprotein belonging to the immunoglobulin superfamily and is essential in the development of the nervous system. It is mainly expressed on neurons and Schwann cells, and plays a key role in axon outgrowth and pathfinding through interactions with various extracellular ligands and intracellular second messenger systems. Mutations in L1 are responsible for a wide spectrum of neurologic abnormalities and mental retardation. This spectrum includes X-linked hydrocephalus, MASA syndrome, X-linked complicated spastic paraplegia type 1 and X-linked agenesis of the corpus callosum. These four diseases were initially described as distinct clinical entities with an overlapping clinical spectrum, but can now be lumped into one syndrome caused by mutations in the L1 gene. The main clinical features of this spectrum are Corpus callosum hypoplasia, mental Retardation, Adducted thumbs, Spastic paraplegia and Hydrocephalus, which has led to the acronym CRASH syndrome.
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PMID:L1-associated diseases: clinical geneticists divide, molecular geneticists unite. 930 Jun 53

The adhesion molecule L1 is a member of the immunoglobulin superfamily. L1 is involved in various recognition processes in the CNS and PNS, and binding to L1 can activate signal transduction pathways. Mutations in the human L1 gene are associated with a variable phenotype, including mental retardation and anomalous development of the nervous system, referred to as 'CRASH' (corpus callosum hypoplasia, retardation, adducted thumbs, spastic paraplegia, and hydrocephalus). We generated an animal model of these conditions by gene targetting. Mutant mice were smaller than wild-type and were less sensitive to touch and pain, and their hind-legs appeared weak and uncoordinated. The size of the corticospinal tract was reduced and, depending on genetic background, the lateral ventricles were often enlarged. Non-myelinating Schwann cells formed processes not associated with axons and showed reduced association with axons. In vitro, neurite outgrowth on an L1 substrate and fasciculation were impaired. The mutant mouse described here will help to elucidate the functions of L1 in the nervous system and how these depend on genetic influences.
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PMID:Disruption of the mouse L1 gene leads to malformations of the nervous system. 935 4

L1 is a neural cell adhesion molecule mainly involved in axon guidance and neuronal migration during brain development. Mutations in the human L1 gene give rise to a complex clinical picture, with mental retardation, neurologic abnormalities and a variable degree of hydrocephalus. Recently, a transgenic mouse model with a targeted null mutation in the L1 gene was generated. These knockout (KO) mice show hypoplasia of the corticospinal tract. Here we have performed further studies of these KO mice including magnetic resonance imaging of the brain, neuropathological analysis and behavioral testing. The ventricular system was shown to be abnormal with dilatation of the lateral ventricles and the 4th ventricle, and an altered shape of the Sylvius aqueduct. Additionally, the cerebellar vermis of the KO mice is hypoplastic. Their exploratory behavior is characterized by stereotype peripheral circling reminiscent of that of rodents with induced cerebellar lesions.
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PMID:L1 knockout mice show dilated ventricles, vermis hypoplasia and impaired exploration patterns. 958 Jun 64

To discover genes contributing to mental retardation in 3p- syndrome patients we have used in silico searches for neural genes in NCBI databases (dbEST and Uni-Gene). An EST with strong homology to the rat CAM L1 gene subsequently mapped to 3p26 was used to isolate a full-length cDNA. Molecular analysis of this cDNA, referred to as CALL (cell adhesion L1-like), showed that it is encoded by a chromosome 3p26 locus and is a novel member of the L1 gene family of neural cell adhesion molecules. Multiple lines of evidence suggest CALL is likely the human ortholog of the murine gene CHL1: it is 84% identical on the protein level, has the same domain structure, same membrane topology, and a similar expression pattern. The orthology of CALL and CHL1 was confirmed by phylogenetic analysis. By in situ hybridization, CALL is shown to be expressed regionally in a timely fashion in the central nervous system, spinal cord, and peripheral nervous system during rat development. Northern analysis and EST representation reveal that it is expressed in the brain and also outside the nervous system in some adult human tissues and tumor cell lines. The cytoplasmic domain of CALL is conserved among other members of the L1 subfamily and features sequence motifs that may involve CALL in signal transduction pathways.
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PMID:In silico-initiated cloning and molecular characterization of a novel human member of the L1 gene family of neural cell adhesion molecules. 979 93

In humans, mutations in the L1 cell adhesion molecule are associated with a neurological syndrome termed CRASH, which includes corpus callosum agenesis, mental retardation, adducted thumbs, spasticity, and hydrocephalus. A mouse model with a null mutation in the L1 gene (Cohen et al., 1997) was analyzed for brain abnormalities by Nissl and Golgi staining and immunocytochemistry. In the motor, somatosensory, and visual cortex, many pyramidal neurons in layer V exhibited undulating apical dendrites that did not reach layer I. The hippocampus of L1 mutant mice was smaller than normal, with fewer pyramidal and granule cells. The corpus callosum of L1-minus mice was reduced in size because of the failure of many callosal axons to cross the midline. Enlarged ventricles and septal abnormalities were also features of the mutant mouse brain. Immunoperoxidase staining showed that L1 was abundant in developing neurons at embryonic day 18 (E18) in wild-type cerebral cortex, hippocampus, and corpus callosum and then declined to low levels with maturation. In the E18 cortex, L1 colocalized with microtubule-associated protein 2, a marker of dendrites and somata. These new findings suggest new roles for L1 in the mechanism of cortical dendrite differentiation, as well as in guidance of callosal axons and regulation of hippocampal development. The phenotype of the L1 mutant mouse indicates that it is a potentially valuable model for the human CRASH syndrome.
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PMID:Abnormalities in neuronal process extension, hippocampal development, and the ventricular system of L1 knockout mice. 1036 25

The neural adhesion molecule L1 mediates the axon outgrowth, adhesion, and fasciculation that are necessary for proper development of synaptic connections. L1 gene mutations are present in humans with the X-linked mental retardation syndrome CRASH (corpus callosum hypoplasia, retardation, aphasia, spastic paraplegia, hydrocephalus). Three missense mutations associated with CRASH syndrome reside in the cytoplasmic domain of L1, which contains a highly conserved binding region for the cytoskeletal protein ankyrin. In a cellular ankyrin recruitment assay that uses transfected human embryonic kidney (HEK) 293 cells, two of the pathologic mutations located within the conserved SFIGQY sequence (S1224L and Y1229H) strikingly reduced the ability of L1 to recruit 270 kDa ankyrinG protein that was tagged with green fluorescent protein (ankyrin-GFP) to the plasma membrane. In contrast, the L1 missense mutation S1194L and an L1 isoform lacking the neuron-specific sequence RSLE in the cytoplasmic domain were as effective as RSLE-containing neuronal L1 in the recruitment of ankyrin-GFP. Ankyrin binding by L1 was independent of cell-cell interactions. Receptor-mediated endocytosis of L1 regulates intracellular signal transduction, which is necessary for neurite outgrowth. In rat B35 neuroblastoma cell lines stably expressing L1 missense mutants, antibody-induced endocytosis was unaffected by S1224L or S1194L mutations but appeared to be enhanced by the Y1229H mutation. These results suggested a critical role for tyrosine residue 1229 in the regulation of L1 endocytosis. In conclusion, specific mutations within key residues of the cytoplasmic domain of L1 (Ser(1224), Tyr(1229)) destabilize normal L1-ankyrin interactions and may influence L1 endocytosis to contribute to the mechanism of neuronal dysfunction in human X-linked mental retardation.
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PMID:Cytoplasmic domain mutations of the L1 cell adhesion molecule reduce L1-ankyrin interactions. 1122 39


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