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)

A novel human gene, TRPC5, was cloned from the region of Xq23 that contains loci for nonsyndromic mental retardation (MRX47 and MRX35) and two genes, DCX and HPAK3, implicated in two X-linked disorders (LISX and MRX30). Within a single YAC, we have determined the order cen-HPAK3(5'-3')-DCX(3'-5')-DXS7012E-TRPC5(3'-5' )-ter. TRPC5 encodes a 974-residue novel human protein (111.5 kDa predicted mass) and displays 99% homology with mouse TRP5, (MGD-approved symbol Trrp5) a novel member of a family of receptor-activated Ca2+ channels. It contains eight transmembrane domains, including a putative pore region. A transcript larger than 9.5 kb is observed only in fetal and adult human brain, with a relatively higher level in the adult human cerebellum. We devised an efficient method, Incorporation PCR SSCP (IPS), for detection of gene alterations. Five single-nucleotide variations in the TRPC5 gene were identified in males with mental retardation. However, these were found to be polymorphic variants. Exclusive expression of the TRPC5 gene in developing and adult brain suggests a possible role during development and provides a candidate gene for instances of mental retardation and other developmental defects.
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PMID:Molecular cloning and characterization of TRPC5 (HTRP5), the human homologue of a mouse brain receptor-activated capacitative Ca2+ entry channel. 1049 32

Calcium is an important second messenger in eukaryotic cells. Many of the effects of calcium are mediated via its interaction with calmodulin and the subsequent activation of Ca(2+)/calmodulin-dependent (CaM) kinases. CaM kinases are involved in a wide variety of cellular processes including muscle contraction, neurotransmitter release, cell cycle control, and transcriptional regulation. While CaMKII has been implicated in learning and memory, the biological role of the other multifunctional CaM kinases, CaMKI and CaMKIV, is largely unknown. In the course of a degenerate RT-PCR protein kinase screen, we identified a novel serine/threonine kinase, Pnck. In this report, we describe the cloning, chromosomal localization, and expression of Pnck, which encodes a 38-kDa protein kinase whose catalytic domain shares 45-70% identity with members of the CaM kinase family. The gene for Pnck localizes to mouse chromosome X, in a region of conserved synteny with human chromosome Xq28 that is associated with multiple distinct mental retardation syndromes. Pnck is upregulated during intermediate and late stages of murine fetal development with highest levels of expression in developing brain, bone, and gut. Pnck is also expressed in a tissue-specific manner in adult mice with highest levels of expression detected in brain, uterus, ovary, and testis. Interestingly, Pnck expression in these tissues is restricted to particular compartments and appears to be further restricted to subsets of cells within those compartments. The chromosomal localization of Pnck, along with its tissue-specific and restricted pattern of spatial expression during development, suggests that Pnck may be involved in a variety of developmental processes including development of the central nervous system.
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PMID:Cloning, characterization, and chromosomal localization of Pnck, a Ca(2+)/calmodulin-dependent protein kinase. 1067 39

Duchenne muscular dystrophy (DMD) and the allelic disorder Becker muscular dystrophy (BMD) are common X-linked recessive neuromuscular disorders that are associated with a spectrum of genetically based developmental cognitive and behavioral disabilities. Seven promoters scattered throughout the huge DMD/BMD gene locus normally code for distinct isoforms of the gene product, dystrophin, that exhibit nervous system developmental, regional and cell-type specificity. Dystrophin is a complex plasmalemmal-cytoskeletal linker protein that possesses multiple functional domains, autosomal and X-linked homologs and associated binding proteins that form multiunit signaling complexes whose composition is unique to each cellular and developmental context. Through additional interactions with a variety of proteins of the extracellular matrix, plasma membrane, cytoskeleton and distinct intracellular compartments, brain dystrophin acquires the capability to participate in the modulatory actions of a large number of cellular signaling pathways. During neural development, dystrophin is expressed within the neural tube and selected areas of the embryonic and postnatal neuraxis, and may regulate distinct aspects of neurogenesis, neuronal migration and cellular differentiation. By contrast, in the mature brain, dystrophin is preferentially expressed by specific regional neuronal subpopulations within proximal somadendritic microdomains associated with synaptic terminal membranes. Increasing experimental evidence suggests that in adult life, dystrophin normally modulates synaptic terminal integrity, distinct forms of synaptic plasticity and regional cellular signal integration. At a systems level, dystrophin may regulate essential components of an integrated sensorimotor attentional network. Dystrophin deficiency in DMD/BMD patients and in the mdx mouse model appears to impair intracellular calcium homeostasis and to disrupt multiple protein-protein interactions that normally promote information transfer and signal integration from the extracellular environment to the nucleus within regulated microdomains. In DMD/BMD, the individual profiles of cognitive and behavioral deficits, mental retardation and other phenotypic variations appear to depend on complex profiles of transcriptional regulation associated with individual dystrophin mutations that result in the corresponding presence or absence of individual brain dystrophin isoforms that normally exhibit developmental, regional and cell-type-specific expression and functional regulation. This composite experimental model will allow fine-level mapping of cognitive-neurogenetic associations that encompass the interrelationships between molecular, cellular and systems levels of signal integration, and will further our understanding of complex gene-environmental interactions and the pathogenetic basis of developmental disorders associated with mental retardation.
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PMID:Brain dystrophin, neurogenetics and mental retardation. 1075 78

Cerebral hypoxia in the fetus and newborn results in neonatal morbidity and mortality as well as long-term sequelae such as mental retardation, seizure disorders, and cerebral palsy. In the developing brain, determinants of susceptibility to hypoxia should include the lipid composition of the brain cell membrane, the rate of lipid peroxidation, the presence of antioxidant defenses, and the development and modulation of excitatory amino acid neurotransmitter receptors such as the N-methyl-D-aspartate (NMDA) receptor, the intracellular Ca2+, and the intranuclear Ca(2+)-dependent mechanisms. In addition to the developmental status of these cellular components, the response of these potential mechanisms to hypoxia determines the fate of the hypoxic brain cell in the developing brain. Using electron spin resonance spectroscopy of alpha-phenyl-N-tert-butyl-nitrone spin adducts, studies from our laboratory demonstrated that tissue hypoxia results in increased free radical generation in the cortex of fetal guinea pigs and newborn piglets. Pretreatment with MgSO4 significantly decreased the hypoxia-induced increase in free radical generation in the term fetal brain. We also showed that brain tissue hypoxia modifies the NMDA receptor ion-channel recognition and modulatory sites. Furthermore, a higher increase in NMDA receptor agonist-dependent Ca2+ in synaptosomes was demonstrated. The increase in intracellular Ca2+ may activate several enzymatic pathways such as phospholipase A2 and metabolism of archidonic acid by cyclooxygenase and lipoxygenase, conversion of xanthine dehydrogenase to xanthine oxidase by proteases, and activation of nitric oxide synthase. Using inhibitors of each of these enzymes such as cyclooxygenase (indomethacin), lipoxygenase (nordihydroguaiaretic acid), xanthine oxidase (allopurinol), and nitric oxide synthase (N-nitro-L-arginine), studies have shown that these enzyme reactions result in oxygen free radical generation, membrane peroxidation, and cell membrane dysfunction in the hypoxic brain. Specifically, generation of nitric oxide free radicals during hypoxia may lead to nitration and nitrosylation of specific membrane proteins and receptors, resulting in dysfunction of receptors and enzymes. We conclude that hypoxia-induced modification of the NMDA receptor leading to increased intracellular Ca2+ results in free radical generation and cell injury. We suggest that during hypoxia the increased intracellular Ca2+ may lead to increased intranuclear Ca2+ concentration and alter nuclear events including transcription of specific apoptotic genes and activation of endonucleases, resulting in programmed cell death.
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PMID:Mechanisms of perinatal cerebral injury in fetus and newborn. 1081 2

The article presents data concerning pseudohypoparathyroidism (PH TP). It is an unusual disease, which is characterized by the resistance of bones and kidney to PTH, followed by hypocalcaemia, hyperphospha-taemia, glandulary hypertrophy and hypersecretion of PTH. Patients with PTHT clinically manifest tetany seizures, soft tissue calcifications and many congenital malformations. The disease has a genetic etiology, it is connected with chromosome X and more often found in women. Clinical symptoms may be different and depend on genetic defect or its selectivity with reference to the tissues. At present we can distinguish three types of PHPT and pseudo-pseudo-HPT. The disease usually appears in the infancy. Early diagnosis and vitamin D3 or calcium treatment seem to be the most important for patient's condition. Too late treatment threatens with brain calcification followed by neurological defects and mental retardation. The long-lasting effect of PTH in bones can lead to their destruction, if bone receptors are completely sensitive.
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PMID:[Pseudohypoparathyroidism]. 1090 70

Disorders of neuronal migration in cerebral cortex are associated with neurological impairments, including mental retardation and epilepsy. Their causes and pathophysiology remain largely unknown, however. In patients with Zellweger disease, a lethal panperoxisomal disorder, and in mice lacking the Pxr1 import receptor for peroxisomal matrix proteins, the absence of peroxisomes leads to abnormal neuronal migration. Analysis of Pxr1-/- mice revealed that the migration defect was caused by altered N-methyl-D-aspartate (NMDA) glutamate receptor-mediated calcium mobilization. This NMDA receptor dysfunction was linked to a deficit in platelet-activating factor, a phenomenon related to peroxisome impairment. These findings confirm NMDA receptor involvement in neuronal migration and suggest a link between peroxisome metabolism and NMDA receptor efficacy.
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PMID:Neuronal migration disorder in Zellweger mice is secondary to glutamate receptor dysfunction. 1097 40

Hyperinsulinism is a rare cause of severe persistent hypoglycaemia in the neonatal period. It is associated with a high incidence of brain damage and mental retardation as a consequence of repeated episodes of hypoglycaemia. Subtotal to near total pancreatectomy is indicated as a matter of urgency to decrease the amount of circulating insulin. The perioperative management of a 45-day-old, 5 kg male infant with hyperinsulinaemia (nesidioblastosis) is described. He had a history of generalized tonic clonic seizures 4 h after birth. The blood sugar at that time was 0.66 mmol x l(-1) (12 mg x dl(-1)) and serum calcium was 2.4 mmol x l(-1) (9.82 mg x dl(-1)). The insulin : glucose ratio was 1.6 (normal < 0.4). Occasional episodes of hypoglycaemia persisted in spite of medical line of management with intravenous dextrose 12%, 2 h gastric tube feeds, hydrocortisone (5 mg x kg(-1) x day(-1) i.v.) and oral diazoxide 10 mg x kg(-1), 8 h for 3 weeks. A CT scan and USG did not reveal any abnormality of the pancreas. However, the EEG varied from one of abnormally low amplitude to an isoelectric record. Renal, liver function tests and coagulation profile were normal. The patient was scheduled for elective subtotal pancreatectomy. The anaesthetic management with emphasis on glucose homeostasis and fluid balance is discussed.
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PMID:Anaesthetic management of a case of nesidioblastosis for subtotal pancreatectomy. 1184 82

Williams syndrome (WS) is the result of a hemideletion of about 17 genes in the q11.22-23 region of chromosome 7. Patients with WS show unique phenotypic features that include elfin face, heart malformations, calcium metabolism problems and learning disorders. The latter consist of mental retardation that is characterised by serious difficulties with processing visuospatial tasks, a striking ability to easily recognise faces, a relatively developed linguistic capacity and sensitiveness to sound, a strong need to establish affective ties with other people and a fondness for music. Anatomical studies show a decrease in the postero-dorsal parts of both hemispheres of the brain, malformation in the central dorsal region and an expansion of the superior temporal gyrus, of the amygdala and of the frontal lobe. These macroscopic anomalies are accompanied by microscopic anomalies, which consist of changes in the number and size of the neurons. Studies on evoked potentials show acoustic hyperexcitability and abnormal waves related to language and to faces. Genetic studies in our laboratories show that the exact size of the deletion can vary, which means partial cases also exist and have partial phenotypes. Combining behavioural, electrophysiological, anatomical and genetic reports suggests a problem with the posterior dorsal region of the brain, possibly resulting from mistakes in establishing the dorsoventral and caudorostral genetico-molecular gradients, which specify the cortical regions during development.
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PMID:[Williams syndrome. A summary of cognitive, electrophysiological, anatomofunctional, microanatomical and genetic findings]. 1259 14

Previously, human genetics-based approaches allowed us to show that mutations in the IL-1 receptor accessory protein-like gene (IL1RAPL) are responsible for a non-specific form of X-linked mental retardation. This gene encodes a predicted protein of 696 amino acids that belongs to a novel class of the IL-1/Toll receptor family. In addition to the extracellular portion consisting of three Ig-like domains and the intracellular TIR domain characteristic of the IL-1/Toll receptor family, IL1RAPL contains a specific 150 amino acid carboxy terminus that has no significant homology with any protein of known function. In order to begin to elucidate the function of this IL-1/Toll receptor-like protein, we have assessed the effect of recombinant IL1RAPL on the binding affinity of type I IL-1R for its ligands IL-1alpha and beta and searched for proteins interacting with the specific carboxy terminus domain of IL1RAPL. Our results show that IL1RAPL is not a protein receptor for IL-1. In addition we present here the identification of Neuronal Calcium Sensor-1 (NCS-1) as an IL1RAPL interactor. Remarkably, although NCS-1 and its non-mammalian homologue, frequenin, are members of a highly conserved EF-hand Ca(2+) binding protein family, our data show that IL1RAPL interacts only with NCS-1 through its specific C-terminal domain. The functional relevance of IL1RAPL activity was further supported by the inhibitory effect on exocytosis in PC12 cells overexpressing IL1RAPL. Taken together, our data suggest that IL1RAPL may regulate calcium-dependent exocytosis and provide insight into the understanding of physiopathological mechanisms underlying cognitive impairment resulting from IL1RAPL dysfunction.
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PMID:IL1 receptor accessory protein like, a protein involved in X-linked mental retardation, interacts with Neuronal Calcium Sensor-1 and regulates exocytosis. 1278 49

Several reports of idiopathic hypercalcemia of childhood have been published since Lightwood in 1932 described dwarfism associated with mental retardation, strabismus, hypercalcemia, nephrocalcinosis and osteosclerosis. The present paper adds two new cases. The first patient was 15 months old when first seen with stunted physical and mental growth, a systolic murmur, and a serum calcium value of 13 mg. %. This child suffered several severe infections and in spite of a low calcium intake and the administration of chelating agents her blood calcium rose until death six months later. The other patient, three years old, also had delayed physical and mental development, typical facies, a systolic murmur, skeletal lesions, and nephrocalcinosis. Varied therapeutic attempts failed.Idiopathic hypercalcemia of childhood is reviewed in the light of the 94 reports already published.
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PMID:[IDIOPATHIC HYPERCALCEMIA IN THE CHILD: 2 NEW CASES AND REVIEW OF THE LITERATURE]. 1407 28


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