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

A locus for X-linked hydrocephalus (HSAS), which is characterized by mental retardation and enlarged brain ventricles, maps to the same subchromosomal region (Xq28) as the gene for neural cell adhesion molecule L1. We have found novel L1 mRNA species in cells from affected members of a HSAS family containing deletions and insertions produced by the utilization of alternative 3' splice sites. A point mutation at a potential branch point signal in an intron segregates with the disease and is likely to be responsible for the abnormal RNA processing. These results suggest that HSAS is a disorder of neuronal cell migration due to disruption of L1 protein function.
 ...
PMID:Aberrant splicing of neural cell adhesion molecule L1 mRNA in a family with X-linked hydrocephalus. 130 58

X-linked hydrocephalus, MASA syndrome and certain forms of X-linked spastic paraplegia and agenesis of corpus callosum are now known to be due to mutations in the gene for the neural cell adhesion molecule L1 (19, 30). As a result, these syndromes have recently been reclassified as CRASH syndrome, an acronym for Corpus callosum hypoplasia, Retardation, Adducted thumbs, Spasticity and Hydrocephalus (8). A comparison of existing case reports with molecular genetic analysis reveals a striking correlation between the type of mutation in the L1CAM gene and the severity of the disease. Mutations that produce truncations in the extracellular domain of the L1 protein are more likely to produce severe hydrocephalus, grave mental retardation or early death than point mutations in the extracellular domain or mutations affecting only the cytoplasmic domain of the protein. While less severe than extracellular truncations, point mutations in the extracellular domain do produce more severe neurologic problems than mutations in just the cytoplasmic domain.
 ...
PMID:CRASH syndrome: mutations in L1CAM correlate with severity of the disease. 926 56

The neural cell adhesion molecule L1 mediates the axon outgrowth, adhesion, and fasciculation necessary for proper development of synaptic connections. Mutations of human L1 cause an X-linked mental retardation syndrome termed CRASH (corpus callosum hypoplasia, retardation, aphasia, spastic paraplegia, and hydrocephalus), and L1 knock-out mice display defects in neuronal process extension resembling the CRASH phenotype. Little is known about the biochemical or cellular mechanism by which L1 performs neuronal functions. Here it is demonstrated that clustering of L1 with antibodies or L1 protein in rodent B35 neuroblastoma and cerebellar neuron cultures induced the phosphorylation/activation of the mitogen-activated protein kinases (MAPKs) and extracellular signal-regulated kinases 1 and 2. MAPK activation was essential for L1-dependent neurite outgrowth, because chemical inhibitors [2-(2'-amino-3'-methoxyphenyl)-oxanaphthalen-4-one and 1,4-diamino-2, 3-dicyano-1,4-bis(2-aminophenylthio)butadiene] of the MAPK kinase MEK strongly suppressed neurite outgrowth by cerebellar neurons on L1. The nonreceptor tyrosine kinase pp60(c-src) was required for L1-triggered MAPK phosphorylation, as shown in src-minus cerebellar neurons and by expression of the kinase-inactive mutant Src(K295M) in B35 neuroblastoma cells. Phosphatidylinositol 3-kinase (PI3-kinase) and the small GTPase p21(rac) were identified as signaling intermediates to MAPK by phosphoinositide and Rac-GTP assays and expression of inhibitory mutants. Antibody-induced endocytosis of L1, visualized by immunofluorescence staining and confocal microscopy of B35 cells, was blocked by expression of kinase-inactive Src(K295M) and dominant-negative dynamin(K44A) but not by inhibitors of MEK or PI3-kinase. Dynamin(K44A) also inhibited L1 antibody-triggered MAPK phosphorylation. This study supports a model in which pp60(c-src) regulates dynamin-mediated endocytosis of L1 as an essential step in MAPK-dependent neurite outgrowth on an L1 substrate.
 ...
PMID:A MAP kinase-signaling pathway mediates neurite outgrowth on L1 and requires Src-dependent endocytosis. 1081 53

Mutations in the L1 neural cell adhesion molecule, a transmembrane glycoprotein, cause a spectrum of congenital neurological syndromes, ranging from hydrocephalus to mental retardation. Many of these mutations are single amino acid changes that are distributed throughout the various domains of the protein. Defective herpes simplex virus vectors were used to express L1 protein with the clinical missense mutations R184Q and D598N in the Ig2 and Ig6 extracellular domains, respectively, and S1194L in the cytoplasmic domain. All three mutant proteins were expressed at similar levels in infected cells. Neurite outgrowth of cerebellar granule cells was stimulated on astrocytes expressing wild-type or S1194L L1, whereas those expressing R184Q and D598N L1 failed to increase neurite length. Live cell immunofluorescent staining of L1 demonstrated that most defective vector-infected cells did not express R184Q or D598N L1 on their cell surface. This greatly diminished cell-surface expression occurred in astrocytes, neurons, and non-neural cells. In contrast to wild-type or S1194L L1, the R184Q and D598N L1 proteins had altered apparent molecular weights and remained completely endoglycosidase H (endoH)-sensitive, suggesting incomplete post-translational processing. We propose that some missense mutations in human L1 impede correct protein trafficking, with functional consequences independent of protein activity. This provides a rationale for how expressed, full-length proteins with single amino acid changes could cause clinical phenotypes similar in severity to knock-out mutants.
 ...
PMID:Clinical mutations in the L1 neural cell adhesion molecule affect cell-surface expression. 1090 8

L1 disease is a group of overlapping clinical phenotypes including X-linked hydrocephalus, MASA syndrome, spastic paraparesis type 1, and X-linked agenesis of corpus callosum. The patients are characterized by hydrocephalus, agenesis or hypoplasia of corpus callosum and corticospinal tracts, mental retardation, spastic paraplegia, and adducted thumbs. The responsible gene, L1CAM, encodes the L1 protein which is a member of the immunoglobulin superfamily of neuronal cell adhesion molecules. The L1 protein is expressed in neurons and Schwann cells and seems to be essential for nervous system development and function. The patients' gene mutations are distributed over the functional protein domains. The exact mechanisms by which these mutations cause a loss of L1 protein function are unknown. There appears to be a relationship between the patients' clinical phenotype and the genotype. Missense mutations in extracellular domains or mutations in cytoplasmic regions cause milder phenotypes than those leading to truncation in extracellular domains or to non-detectable L1 protein. Diagnosis of patients and carriers, including prenatal testing, is based on the characteristic clinical picture and DNA mutation analyses. At present, there is no therapy for the prevention or cure of patients' neurological disabilities.
 ...
PMID:Genetic and clinical aspects of X-linked hydrocephalus (L1 disease): Mutations in the L1CAM gene. 1143 88

Mutations in L1CAM, the gene encoding the transmembrane multifunctional neuronal adhesion molecule L1, are associated with neurodevelopmental disorders including X-linked hydrocephalus and mental retardation. Some amino acid substitutions in various extracellular domains of L1 are known to affect posttranslational processing of the protein or its homophilic and heterophilic interactions. It is largely unknown, however, how these mutations result in neurodevelopmental disturbances and whether the effects of mutations on neurodevelopment can be modeled in vitro. We stably expressed full-length human wild type L1 and the known pathogenic missense mutations I179S, R184W, Y194C, and C264Y in NIH-3T3 cells. L1 protein synthesis, glycosylation pattern, and subcellular localization were analyzed. Neurite outgrowth of primary murine cerebellar neurons was measured after 23 hrs of co-cultivation using transfected NIH-3T3 cells as substrate. Like wild type L1, L1 protein with I179S or Y194C mutations was localized on the surface of the transfected substrate cells, but this was not the case with R184W or C264Y mutations. All four mutations were associated with reduced stimulation of neurite outgrowth. Measurement of neurite outgrowth on transfected substrate cells may be a suitable model for studying neurodevelopmental disturbances.
 ...
PMID:Missense mutations in the extracellular domain of the human neural cell adhesion molecule L1 reduce neurite outgrowth of murine cerebellar neurons. 1244 87

Mutations in the human L1CAM gene cause X-linked hydrocephalus and MASA (Mental retardation, Aphasia, Shuffling gait, Adducted thumbs) syndrome. In vitro studies have shown that the L1 cytoplasmic domain (L1CD) is involved in L1 trafficking, neurite branching, signaling, and interactions with the cytoskeleton. L1cam knockout (L1(KO)) mice have hydrocephalus, a small cerebellum, hyperfasciculation of corticothalamic tracts, and abnormal peripheral nerves. To explore the function of the L1CD, we made three new mice lines in which different parts of the L1CD have been altered. In all mutant lines L1 protein is expressed and transported into the axon. Interestingly, these new L1CD mutant lines display normal brain morphology. However, the expression of L1 protein in the adult is dramatically reduced in the two L1CD mutant lines that lack the ankyrin-binding region and they show defects in motor function. Therefore, the L1CD is not responsible for the major defects observed in L1(KO) mice, yet it is required for continued L1 protein expression and motor function in the adult.
 ...
PMID:Role of the cytoplasmic domain of the L1 cell adhesion molecule in brain development. 2012 21

L1 syndrome is a group of overlapping, X-linked disorders caused by mutations in L1CAM. Clinical phenotypes within L1 syndrome include X-linked hydrocephalus with stenosis of the aqueduct of sylvius (HSAS); mental retardation, adducted thumbs, shuffling gait, and aphasia (MASA) syndrome; spastic paraplegia type 1; and agenesis of the corpus callosum. Over 200 mutations in L1CAM have been reported; however, only a few large gene deletions have been observed. We report on a 4-month-old male with a de novo whole gene deletion of L1CAM presenting with congenital hydrocephalus, aqueductal stenosis, and adducted thumbs. Initial failure of L1CAM gene sequencing suggested the possibility of a whole gene deletion of L1CAM. Further investigation through chromosome microarray analysis showed a 62Kb deletion encompassing the first exon of the PDZD4 gene and the entire L1CAM gene. Investigations into genotype-phenotype correlations have suggested that mutations leading to truncated or absent L1 protein cause more severe forms of L1 syndrome. Based on the presentation of the proband and other reported patients with whole gene deletions, we provide further evidence that L1CAM whole gene deletions result in L1 syndrome with a severe phenotype, deletions of PDZD4 do not cause additional manifestations, and that X-linked nephrogenic diabetes insipidus reported in a subset of patients with large L1CAM deletions results from the loss of AVPR2.
 ...
PMID:L1CAM whole gene deletion in a child with L1 syndrome. 2466 63