Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004352 (autism)
 32,579 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ca2+ has been proposed to regulate Na+ channels through the action of calmodulin (CaM) bound to an IQ motif or through direct binding to a paired EF hand motif in the Nav1 C terminus. Mutations within these sites cause cardiac arrhythmias or autism, but details about how Ca2+ confers sensitivity are poorly understood. Studies on the homologous Cav1.2 channel revealed non-canonical CaM interactions, providing a framework for exploring Na+ channels. In contrast to previous reports, we found that Ca2+ does not bind directly to Na+ channel C termini. Rather, Ca2+ sensitivity appears to be mediated by CaM bound to the C termini in a manner that differs significantly from CaM regulation of Cav1.2. In Nav1.2 or Nav1.5, CaM bound to a localized region containing the IQ motif and did not support the large Ca(2+)-dependent conformational change seen in the Cav1.2.CaM complex. Furthermore, CaM binding to Nav1 C termini lowered Ca2+ binding affinity and cooperativity among the CaM-binding sites compared with CaM alone. Nonetheless, we found suggestive evidence for Ca2+/CaM-dependent effects upon Nav1 channels. The R1902C autism mutation conferred a Ca(2+)-dependent conformational change in Nav1.2 C terminus.CaM complex that was absent in the wild-type complex. In Nav1.5, CaM modulates the Cterminal interaction with the III-IV linker, which has been suggested as necessary to stabilize the inactivation gate, to minimize sustained channel activity during depolarization, and to prevent cardiac arrhythmias that lead to sudden death. Together, these data offer new biochemical evidence for Ca2+/CaM modulation of Na+ channel function.
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PMID:Calmodulin mediates Ca2+ sensitivity of sodium channels. 1531 14

Timothy syndrome (TS) is a multisystem disorder that causes syncope and sudden death from cardiac arrhythmias. Prominent features include congenital heart disease, immune deficiency, intermittent hypoglycemia, cognitive abnormalities, and autism. All TS individuals have syndactyly (webbing of fingers and toes). We discovered that TS resulted from a recurrent, de novo cardiac L-type calcium channel (CaV1.2) mutation, G406R. G406 is located in alternatively spliced exon 8A, encoding transmembrane segment S6 of domain I. Here, we describe two individuals with a severe variant of TS (TS2). Neither child had syndactyly. Both individuals had extreme prolongation of the QT interval on electrocardiogram, with a QT interval corrected for heart rate ranging from 620 to 730 ms, causing multiple arrhythmias and sudden death. One individual had severe mental retardation and nemaline rod skeletal myopathy. We identified de novo missense mutations in exon 8 of CaV1.2 in both individuals. One was an analogous mutation to that found in exon 8A in classic TS, G406R. The other mutation was G402S. Exon 8 encodes the same region as exon 8A, and the two are mutually exclusive. The spliced form of CaV1.2 containing exon 8 is highly expressed in heart and brain, accounting for approximately 80% of CaV1.2 mRNAs. G406R and G402S cause reduced channel inactivation, resulting in maintained depolarizing L-type calcium currents. Computer modeling showed prolongation of cardiomyocyte action potentials and delayed afterdepolarizations, factors that increase risk of arrhythmia. These data indicate that gain-of-function mutations of CaV1.2 exons 8 and 8A cause distinct forms of TS.
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PMID:Severe arrhythmia disorder caused by cardiac L-type calcium channel mutations. 1586 12

Milk from dairy cows has long provided a high quality source of protein and selected micronutrients such as calcium to most populations. Recently, a relationship between disease risk and consumption of a specific bovine ss-casein fraction either A1 or A2 genetic variants has been identified. Populations, which consume milk containing high levels of ss-casein A2 variant, have a lower incidence of cardiovascular disease and type 1 diabetes. Furthermore, consumption of milk with the A2 variant may be associated with less severe symptoms of autism and schizophrenia. The mechanism of action focuses on ss-casein A1 and related forms preferentially that are able to produce a bioactive opioid peptide, ss-casomorphin-7 (ss-CM-7) during digestion. Infants may absorb ss-CM-7 due to an immature gastrointestinal tract. Adults, on the other hand, appear to reap the biological activity locally on the intestinal brush boarder. ss-CM-7 can potentially affect numerous opioid receptors in the nervous, endocrine, and immune systems. Whether there is a definite health benefit to milk containing the A2 genetic variant is unknown and requires further investigation.
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PMID:Health implications of milk containing beta-casein with the A2 genetic variant. 1640 84

The mammalian bombesin (BB)-like peptide gastrin-releasing peptide (GRP) stimulates cell proliferation, displays a range of neuroendocrine activities, and acts as a growth factor in the pathogenesis of several types of human cancer. Several lines of evidence have indicated that GRP and its receptor (GRPR) might also be involved in the neurochemical alterations associated with psychiatric and neurological disorders. GRP and GRPR are distributed throughout the mammalian central nervous system (CNS). Altered levels of BB-like peptides have been found in the CNS of patients with schizophrenia and Parkinson's disease. Dysfunctions in GRPR-induced cellular calcium signaling have been reported in fibroblasts from patients with Alzheimer's disease. A translocation in the GRPR gene has been associated with autism. Pharmacological and genetic studies in rodents have shown that GRPRs in brain areas such as the dorsal hippocampus and amygdala are importantly involved in regulating synaptic plasticity and aspects of behavior that might be altered in disorders such as anxiety, schizophrenia, depression, autism and dementia. Behaviors modulated by the GRPR in rodents include grooming, food intake, stereotypy, social behavior, and emotionally-motivated learning and memory. Together, these findings support the view that the GRPR should be considered a therapeutic target for a subset of CNS diseases.
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PMID:Gastrin-releasing peptide receptor as a molecular target for psychiatric and neurological disorders. 1661 Oct 92

Previous studies reported positive results with the use of Mg-vitamin B6 in autism. Despite these reports, this intervention remains controversial. In order to study relationships between changes in clinical symtoms and biological parameters, 33 children (mean age: 4 [1-10] years old) with clinical symptoms of pervasive developmental disorder or autism (PDD, as defined in DSM-IV) were followed for at least 6 months; another group of 36 children (same age) devoided of any known pathology was used as control. All PDD children received a magnesium-vit B6 (Mg-B6) regimen (6 mg/kg/d Mg and 0.6 mg/kg/d vit B6). Intraerythrocyte Mg2+ (Erc-Mg), serum Mg2+ (s-Mg) and blood ionized Ca2+ (i-Ca) were measured before and after treatment. Clinical symptoms of PDD were scored (0 to 4). In contrast to s-Mg or i-Ca, PDD children exhibited significantly lower Erc-Mg values than controls (2.17 +/- 0.4 versus 2.73 +/- 0.23 mmol/L; 16/33). The Mg-B6 regimen led to an increase in Erc-Mg values (2.42 +/- 0.41 (after) versus 2.17 +/- 0.4 mmol/l (before), 11/17) and this supplementation improved PDD symptoms in 23/33 children (p < 0.0001) with no adverse effects: social interactions (23/33), communication (24/33), stereotyped restricted behavior (18/33), and abnormal/delayed functioning (17/33); 15/33 children were improved in the first three groups of symptoms. When the Mg-B6 treatment was stopped, PDD symtoms reappeared in few weeks. A statistically significant relationship was found in Erc-Mg values from children before treatment and their mothers. In conclusion, this study suggests that the behavioral improvement observed with the combination vitamin B6-magnesium in PDD/autism is associated with concomitant modifications of Erc-Mg values.
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PMID:Improvement of neurobehavioral disorders in children supplemented with magnesium-vitamin B6. II. Pervasive developmental disorder-autism. 1684 1

The present study was undertaken to evaluate the nutritional status of children with special needs in Alexandria city, on the basis of nutrient intake and food consumption. Socio-demographic characteristics and dietary data were determined in a sample of 231 disabled children chosen randomly from five specialized day care centers. Results showed that the age of the sample ranged from less than 7 to 24 years with a mean age of 12.6 +/- 4.7 years. Mental retardation represents the highest proportion of subjects followed by Down's syndrome and then Autism Male subjects were found to consume higher nutrients than females at all ages except age under seven years. The intake of both gender was less than the recommended for energy, calcium, vitamin A, niacin and zinc. While the intake of protein and vitamin C was more than the RDA Iron intake was below the recommended for females at all ages and within the acceptable level for male. The results also showed that there is a relationship between nutrient intake and disability type. Down syndrome children were found to consume more nutrients than mentally retarded and autistic subjects.
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PMID:Assessment of the nutritional status of children with special needs in Alexandria: I. Nutrient intake and food consumption. 1691 48

Autism spectrum disorders (ASDs) are a group of developmental disorders characterized by social and emotional deficits, language impairments and stereotyped behaviors that manifest in early postnatal life. The molecular mechanisms that underlie ASDs are not known, but several recent developments suggest that some forms of autism are caused by failures in activity-dependent regulation of neural development. Mutations of several voltage-gated and ligand-gated ion channels that regulate neuronal excitability and Ca2+ signaling have been associated with ASDs. In addition, Ca2+-regulated signaling proteins involved in synapse formation and dendritic growth have been implicated in ASDs. These recent advances suggest a set of signaling pathways that might have a role in generating these increasingly prevalent disorders.
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PMID:Molecular mechanisms of autism: a possible role for Ca2+ signaling. 1727 85

Aralar is a mitochondrial calcium-regulated aspartate-glutamate carrier mainly distributed in brain and skeletal muscle, and involved in the transport of aspartate from mitochondria to the cytosol of a cell. Studies have shown that the brain N-acetyl aspartate (NAA) levels are greatly decreased in aralar-deficient mice, suggesting that aralar plays an important role in the synthesis of NAA in neuronal cells. Since magnetic resonance spectroscopy studies have revealed consistently reduced NAA levels in various brain regions of schizophrenic patients and their unaffected relatives, genes that affect aralar levels or NAA metabolism in the brain may be implicated in the pathogenesis of schizophrenia. Aralar is encoded by the SLC25A12 gene. In the past this gene has been found to be associated with susceptibility to autism; in this study we tested the hypothesis that SLC25A12 genetic variants confer susceptibility to schizophrenia. Six SLC25A12 polymorphisms were studied in a sample population of 253 people with schizophrenia and 216 normal controls. Significant linkage disequilibrium was obtained among the six polymorphisms. However, neither single marker nor haplotype analysis revealed an association between variants at the SLC25A12 locus and schizophrenia, suggesting that it is unlikely that the SLC25A12 polymorphisms investigated play a substantial role in conferring susceptibility to schizophrenia in the Chinese population. Further studies with SLC25A12 variants relating to brain NAA levels in patients with schizophrenia are suggested.
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PMID:Association study of polymorphisms in the mitochondrial aspartate/glutamate carrier SLC25A12 (aralar) gene with schizophrenia. 1769 6

The heterophilic synaptic adhesion molecules neuroligins and neurexins are essential for establishing and maintaining neuronal circuits by modulating the formation and maturation of synapses. The neuroligin-neurexin adhesion is Ca2+-dependent and regulated by alternative splicing. We report a structure of the complex at a resolution of 2.4 A between the mouse neuroligin-1 (NL1) cholinesterase-like domain and the mouse neurexin-1beta (NX1beta) LNS (laminin, neurexin and sex hormone-binding globulin-like) domain. The structure revealed a delicate neuroligin-neurexin assembly mediated by a hydrophilic, Ca2+-mediated and solvent-supplemented interface, rendering it capable of being modulated by alternative splicing and other regulatory factors. Thermodynamic data supported a mechanism wherein splicing site B of NL1 acts by modulating a salt bridge at the edge of the NL1-NX1beta interface. Mapping neuroligin mutations implicated in autism indicated that most such mutations are structurally destabilizing, supporting deficient neuroligin biosynthesis and processing as a common cause for this brain disorder.
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PMID:Structural basis for synaptic adhesion mediated by neuroligin-neurexin interactions. 1808 3

The neuroligins are postsynaptic cell adhesion proteins whose associations with presynaptic neurexins participate in synaptogenesis. Mutations in the neuroligin and neurexin genes appear to be associated with autism and mental retardation. The crystal structure of a neuroligin reveals features not found in its catalytically active relatives, such as the fully hydrophobic interface forming the functional neuroligin dimer; the conformations of surface loops surrounding the vestigial active center; the location of determinants that are critical for folding and processing; and the absence of a macromolecular dipole and presence of an electronegative, hydrophilic surface for neurexin binding. The structure of a beta-neurexin-neuroligin complex reveals the precise orientation of the bound neurexin and, despite a limited resolution, provides substantial information on the Ca2+-dependent interactions network involved in trans-synaptic neurexin-neuroligin association. These structures exemplify how an alpha/beta-hydrolase fold varies in surface topography to confer adhesion properties and provide templates for analyzing abnormal processing or recognition events associated with autism.
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PMID:Structural analysis of the synaptic protein neuroligin and its beta-neurexin complex: determinants for folding and cell adhesion. 1809 22


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