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)

Mental retardation, hydrocephalus, and agenesis of the corpus callosum are observed both in fetal alcohol syndrome (FAS) and in children with mutations in the gene for the cell adhesion molecule L1. We studied the effects of ethanol on cell-cell adhesion in mouse fibroblasts transfected with human L1. L1-transfected fibroblasts exhibited increased cell-cell adhesion compared with wild-type or vector-transfected controls. Ethanol potently and completely inhibited L1-mediated adhesion both in transfected L cells and NIH/3T3 cells. Half-maximal inhibition was observed at 7 mM ethanol, a concentration achieved in blood and brain after ingesting one alcoholic beverage. In contrast, ethanol did not inhibit the adhesion of fibroblasts transfected with vector alone or with N-CAM-140. L1-mediated cell-cell adhesion was inhibited with increasing potency by n-propanol and n-butanol, but was not inhibited at all by n-alcohols of 5 to 8 carbons, acetaldehyde, or acetate, suggesting that ethanol interacts directly with a small hydrophobic pocket within L1. Phenylalanine, teratogenic anticonvulsants, and high concentrations of glucose did not inhibit L1-mediated cell-cell adhesion. Ethanol also inhibited potently the heterotypic adhesion of rat cerebellar granule cells to a monolayer of L1-transfected NIH/3T3 cells, but had no effect on their adhesion to N-CAM-140 or vector-transfected NIH/3T3 cells. Because L1 plays a role in both neural development and learning, ethanol inhibition of L1-mediated cell-cell interactions could contribute to FAS and ethanol-associated memory disorders.
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PMID:Alcohol inhibits cell-cell adhesion mediated by human L1. 860 70

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

X-linked hydrocephalus is a genetic form of hydrocephalus that frequently occurs in females. It is characterized by ventricular dilatation, mental retardation, deformity of the thumb and spastic paraparesis. Recently, 23 different mutations of the gene for the neural cell adhesion molecule, L1CAM, located at chromosome region Xq28, have been reported, 16 of which were detected in families with X-linked hydrocephalus. We sequenced the coding region of the L1CAM gene of patients from two different families with X-linked hydrocephalus and found a novel mutation at nucleotide residue 1963 in one family. This mutation from adenine to guanine results in an amino acid change from lysine to glutamic acid at residue 655 of the L1CAM protein, which belongs to the fibronectin type III domain. We report another method of the rapid identification of the mutation based on the polymerase chain reaction. This mutation was not detected among 70 X chromosomes from a healthy population. Ours is the first report demonstrating this gene mutation in X-linked hydrocephalus in an Asian population. Our findings further emphasize the evolving genotypic heterogeneity in X-linked hydrocephalus.
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PMID:A new mutation of the L1CAM gene in an X-linked hydrocephalus family. 911 41

The L1 cell adhesion molecule (L1CAM) is a neuronal gene involved in the development of the nervous system. Mutations in L1CAM are known to cause several clinically overlapping X linked mental retardation conditions: X linked hydrocephalus (HSAS), MASA syndrome (mental retardation, aphasia, shuffling gait, adducted thumbs), spastic paraplegia type I (SPG1), and X linked agenesis of the corpus callosum (ACC). In an analysis of a family with HSAS, we identified a C-->T transition (C924T) in exon 8 that was initially thought to have no effect on the protein sequence as the alteration affected the third base of a codon (G308G). Extensive analysis of the other 27 exons showed no other alteration. A review of the sequence surrounding position 924 indicated that the C-->T transition created a potential 5' splice site consensus sequence, which would result in an in frame deletion of 69 bp from exon 8 and 23 amino acids of the L1CAM protein. RT-PCR of the RNA from an affected male fetus and subsequent sequence analysis confirmed the use of the new splice site. This is the first report of a silent nucleotide substitution in L1CAM giving rise to an alteration at the protein level. Furthermore, it shows that as mutation analysis plays an ever more important role in human genetics, the identification of a synonymous base change should not be routinely discounted as a neutral polymorphism.
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PMID:A silent mutation, C924T (G308G), in the L1CAM gene results in X linked hydrocephalus (HSAS). 964 85

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

Neural cell adhesion molecule L1 is an important molecule mediating cell-cell interactions during the development of nervous system. L1 can promote axonal outgrowth and is related with nerve cell migration, and therefore L1 plays an important role both in the development and maintaince of the nervous system. In humans, mutations in the L1 gene can lead to mental retardation, spastic paraplegia, hydrocephalus, and other developmental abnormalities. The molecular mechanisms of mutations in L1 gene to induce inherited neurological diseases are not clear. In present investigation, a transgenic DNA of mouse L1 extracellular domain (L1ECD) was constructed by adding a stop codon to the end of L1ECD cDNA and then putting it under the control of CAMK II promoter, which is active specifically in the brain. To verify this construct, L1ECD cDNA was subcloned into an expression vector pCEP4 and then transfected the C6 cells. The expression of L1ECD cDNA in C6 cells was confirmed by Northern blotting and the effects of L1ECD on the growth rate and morphology of C6 cells in vitro as well as primarily cultured neurons were observed. The L1ECD constructs were microinjected into the fertilized zygotes of C57BL/6 mice. The transgenic mice thus produced were identified by Southern and Northern hybridization analysis. The results demonstrated that the L1ECD was integrated in the genome of transgenic mice and expressed specifically in the brain.
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PMID:[Effect of L1ECD on mouse primarily cultured neurons and construction of transgenic mice specifically expressing L1ECD in brain]. 1254 2

Mutations in the X-chromosomal gene (L1CAM) for cell adhesion molecule L1 are associated with a heterogeneous group of conditions that include agenesis of the corpus callosum, hydrocephalus, spastic paraplegia, adducted thumbs and mental retardation (L1-spectrum disease, CRASH or MASA syndrome). Although L1CAM is expressed during renal development and L1cam-deficient mice have congenital malformations of the kidney and the urinary tract, L1CAM mutations have not been associated with renal anomalies in men. We report on a boy with prenatally detected hydrocephalus. After his birth, bilateral duplex kidneys and ureters, with a unilateral mega-ureter serving a hydronephrotic upper pole, as well as agenesis of the corpus callosum, adducted thumbs, spasticity, and mental retardation were recognized, fulfilling the criteria of an L1-spectrum disease. Genetic testing of the patient and his mother identified a 2 bp deletion in the invariant splice consensus sequence of intron 18 of L1CAM, predicting a largely truncated or absent protein. At the age of 9 years, 7 years after heminephrectomy, the boy has normal renal function. This observation suggests that patients with L1CAM mutations may have renal abnormalities as seen in the L1cam-deficient mouse model. L1CAM might, therefore, also be considered a possible candidate gene for renal malformations.
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PMID:L1CAM mutation in a boy with hydrocephalus and duplex kidneys. 1729 22

Research over the last 25 years on the cell adhesion molecule L1 has revealed its pivotal role in nervous system function. Mutations of the human L1CAM gene have been shown to cause neurodevelopmental disorders such as X-linked hydrocephalus, spastic paraplegia and mental retardation. Impaired L1 function has been also implicated in the aetiology of fetal alcohol spectrum disorders, defective enteric nervous system development and malformations of the renal system. Importantly, aberrant expression of L1 has emerged as a critical factor in the development of human carcinomas, where it enhances cell proliferation, motility and chemoresistance. This discovery promoted collaborative work between tumour biologists and neurobiologists, which has led to a substantial expansion of the basic knowledge about L1 function and regulation. Here we provide an overview of the pathological conditions caused by L1 malfunction. We further discuss how the available data on gene regulation, molecular interactions and posttranslational processing of L1 may contribute to a better understanding of associated neurological and cancerous diseases.
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PMID:L1CAM malfunction in the nervous system and human carcinomas. 2023 19

Martin-Bell syndrome is mainly caused by the expansion of CGG trinucleotide repeats (>200 CGG) in the first exon of the FMR1 gene, leading to hypermethylation of the promoter region and silencing of the FMR1 protein expression. These changes are responsible for a phenotype with varying degrees of mental retardation, a long face with large and protruding ears, macroorchidism and autistic behavior. There may also be, however, patients who exhibit typical features of the syndrome without any expansion in the FMR1 gene; thus, other mechanisms affecting the expression of the FMR1 gene were assessed in 25 out of 29 ascertained patients with the typical phenotype without full mutation. Promoter methylation status of FMR1, mutations in its sequence and copy number variations (CNVs) in genes associated with intellectual disability were investigated. In 25 independent male patients without expansion, the promoter region was unmethylated; one patient with a full mutation showed methylation mosaicism; and a female patient had 81.2% of CpG sites methylated and 18.8% hemimethylated. One heterozygous duplication in exon 6 of the PDCD6 gene (programmed cell death 6) and a heterozygous deletion in exon 5 of the CHL1 gene (cell adhesion molecule L1), respectively, were found in two independent patients.
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PMID:Most Martin-Bell syndrome (FMR1-related disorder) Venezuelan patients did not show CGG expansion but instead display genetic heterogeneity. 2770 71