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)

Congenital insensitivity to pain with anhidrosis (CIPA; MIM 256800) is an autosomal-recessive disorder characterized by recurrent episodes of unexplained fever, anhidrosis (absence of sweating) and absence of reaction to noxious stimuli, self-mutilating behaviour and mental retardation. The genetic basis for CIPA is unknown. Nerve growth factor (NGF) induces neurite outgrowth and promotes survival of embryonic sensory and sympathetic neurons. Mice lacking the gene for TrkA, a receptor tyrosine kinase for NGF, share dramatic phenotypic features of CIPA, including loss of responses to painful stimuli, although anhidrosis is not apparent in these animals. We therefore considered the human TRKA homologue as a candidate for the CIPA gene. The mRNA and genomic DNA encoding TRKA were analysed in three unrelated CIPA patients who had consanguineous parents. We detected a deletion-, splice- and missense-mutation in the tyrosine kinase domain in these three patients. Our findings strongly suggest that defects in TRKA cause CIPA and that the NGF-TRKA system has a crucial role in the development and function of the nociceptive reception as well as establishment of thermoregulation via sweating in humans. These results also implicate genes encoding other TRK and neurotrophin family members as candidates for developmental defect(s) of the nervous system.
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PMID:Mutations in the TRKA/NGF receptor gene in patients with congenital insensitivity to pain with anhidrosis. 869 25

Williams syndrome (SW) is a rare (2-5/100,000) genetic human disorder characterised by a typical facies and mental retardation with a deficit in the visuo-spatial cognitive function and a relative preservation of linguistic abilities. This syndrome also includes morphological anomalies and metabolic-functional impairments, likely deficits in the pattern of brain ontogenesis. Neuropsychological and somatic features of the SW individuals are illustrated, and the correspondent genetic bases, recently identified, are presented. The possible role of NGF (nerve growth factor), a particular neurotrophin involved in the development of brain cholinergic system and the associated behavioural functions, in the aetiology of the typical mental retardation of SW patients, is critically discussed. Prospect of researches, including the identification of potential neurobiological markers and the definition of appropriate cognitive profiles of the SW, in order to precociously diagnose this syndrome, and a more thorough investigation of factors affecting phenotypic expression of this genetically determined pathological condition, are reviewed.
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PMID:[Williams syndrome: a window to the development of cognitive and neural processes]. 947 Feb 50

Congenital insensitivity to pain with anhidrosis (CIPA) is characterized by recurrent episodes of unexplained fever, anhidrosis (inability to sweat), absence of reaction to noxious stimuli, self-mutilating behavior, and mental retardation. Human TRKA encodes a high-affinity tyrosine kinase receptor for nerve growth factor (NGF), a member of the neurotrophin family that induces neurite outgrowth and promotes survival of embryonic sensory and sympathetic neurons. We have recently demonstrated that TRKA is responsible for CIPA by identifying three mutations in a region encoding the intracellular tyrosine kinase domain of TRKA in one Ecuadorian and three Japanese families. We have developed a comprehensive strategy to screen for TRKA mutations, on the basis of the gene's structure and organization. Here we report 11 novel mutations, in seven affected families. These are six missense mutations, two frameshift mutations, one nonsense mutation, and two splice-site mutations. Mendelian inheritance of the mutations is confirmed in six families for which parent samples are available. Two mutations are linked, on the same chromosome, to Arg85Ser and to His598Tyr;Gly607Val, hence, they probably represent double and triple mutations. The mutations are distributed in an extracellular domain, involved in NGF binding, as well as the intracellular signal-transduction domain. These data suggest that TRKA defects cause CIPA in various ethnic groups.
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PMID:Congenital insensitivity to pain with anhidrosis: novel mutations in the TRKA (NTRK1) gene encoding a high-affinity receptor for nerve growth factor. 1033 Mar 44

Williams syndrome (WS) is a rare (2-5/100,000) genetic human disorder characterised by a typical facies and mental retardation with a deficit in the visuospatial cognitive function and a relative preservation of linguistic abilities in general, and spoken language in particular. This syndrome also includes morphological anomalies, metabolic functional impairments, and likely deficits in the pattern of brain ontogenesis. The genetic basis of WS, recently identified, are presented. A cognitive profile of the WS individuals is defined and compared to Down syndrome (DS) and autism cognitive profiles. Neuroanatomical features of WS, including a reduction in brain volume, preservation of cerebellum and frontal lobes, and a reduction of posterior cortical systems, are described. The possible role of NGF (nerve growth factor)--a neurotrophin involved in the development of brain cholinergic systems and the associated behavioural functions--in the aetiology of the typical mental retardation of WS patients, is critically discussed. Future research avenues, including the identification of potential neurobiological markers in order to precociously diagnose this syndrome, are reviewed.
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PMID:[Williams syndrome]. 1064 54

Foetal alcohol syndrome is a known cause of mental retardation. It has been suggested that the anatomical and functional alterations observed in the cerebral cortex could be mediated by an interference of ethanol with developmental processes modulated by neurotrophins and/or their receptors. We have studied by immunohistochemistry the expression of the p75 neurotrophin receptor (p75 NTR) in the sensori-motor cortex of P10 and P20 rats exposed to the inhalation of ethanol during the first week of postnatal life. At both the studied ages, the number of p75 NTR immunoreactive neurons was higher in ethanol treated animals compared to controls. The increase of immunoreactive elements was relatively more marked in the motor than in the somatosensory cortex. The involvement of p75 NTR in ethanol-induced apoptosis and neural plasticity is discussed.
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PMID:Overexpression of the p75 neurotrophin receptor in the sensori-motor cortex of rats exposed to ethanol during early postnatal life. 1272 25

Mice rendered null for alpha-dystrobrevin, a component of the dystrophin complex, have muscular dystrophy, despite the fact that the sarcolemma remains relatively intact (Grady, R. M., Grange, R. W., Lau, K. S., Maimone, M. M., Nichol, M. C., Stull, J. T., and Sanes, J. R. (1999) Nat. Cell Biol. 1, 215-220) Thus, alpha-dystrobrevin may serve a signaling function that is important for the maintenance of muscle integrity. We have identified a new dystrobrevin-associated protein, DAMAGE, that may play a signaling role in brain, muscle, and peripheral nerve. In humans, DAMAGE is encoded by an intronless gene located at chromosome Xq13.1, a locus that contains genes involved in mental retardation. DAMAGE associates directly with alpha-dystrobrevin, as shown by yeast two-hybrid, and co-immunoprecipitates with the dystrobrevin-syntrophin complex from brain. This co-immunoprecipitation is dependent on the presence of alpha-dystrobrevin but not beta-dystrobrevin. The DAMAGE protein contains a potential nuclear localization signal, 30 12-amino acid repeats, and two MAGE homology domains. The domain structure of DAMAGE is similar to that of NRAGE, a MAGE protein that mediates p75 neurotrophin receptor signaling and neuronal apoptosis (Salehi, A. H., Roux, P. P., Kubu, C. J., Zeindler, C., Bhakar, A., Tannis, L. L., Verdi, J. M., and Barker, P. A. (2000) Neuron 27, 279-288). DAMAGE is highly expressed in brain and is present in the cell bodies and dendrites of hippocampal and Purkinje neurons. In skeletal muscle, DAMAGE is at the postsynaptic membrane and is associated with a subset of myonuclei. DAMAGE is also expressed in peripheral nerve, where it localizes along with other members of the dystrophin complex to the perineurium and myelin. These results expand the role of dystrobrevin and the dystrophin complex in membrane signaling and disease.
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PMID:DAMAGE, a novel alpha-dystrobrevin-associated MAGE protein in dystrophin complexes. 1462 85

Congenital insensitivity to pain with anhidrosis or hereditary sensory and autonomic neuropathy type IV (HSAN IV) is the first human genetic disorder implicated in the neurotrophin signal transduction pathway. HSAN IV is characterized by absence of reaction to noxious stimuli, recurrent episodes of fever, anhidrosis, self-mutilating behavior and often mental retardation. Mutations in the neurotrophic tyrosine kinase, receptor, type 1 (NTRK1) are associated with this disorder. Here we report four homozygous mutations, two frameshift (p.Gln626fsX6 and p.Gly181fsX58), one missense (p.Arg761Trp) and one splice site (c.359+5G>T) mutation in four HSAN IV patients. The splice site mutation caused skipping of exons 2 and 3 in patient's mRNA resulting in an in-frame deletion of the second leucine-rich motif. NTRK1 mutations are only rarely reported in the European population. This report extends the spectrum of NTRK1 mutations observed in patients diagnosed with HSAN IV.
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PMID:Novel frameshift and splice site mutations in the neurotrophic tyrosine kinase receptor type 1 gene (NTRK1) associated with hereditary sensory neuropathy type IV. 1637 86

In addition to their prominent role as survival signals for neurons in the developing nervous system, neurotrophins have established their significance in the adult brain as well, where their modulation of synaptic transmission and plasticity may participate in associative learning and memory. These crucial activities are primarily the result of neurotrophin regulation of intracellular Ca(2+) homeostasis and, ultimately, changes in gene expression. Outlined in the following review is a synopsis of neurotrophin signaling with a particular focus upon brain-derived neurotrophic factor (BDNF) and its role in hippocampal synaptic plasticity and neuronal Ca(2+) homeostasis. Neurotrophin signaling through tropomyosin-related kinase (Trk) and pan-neurotrophin receptor 75 kD (p75(NTR)) receptors are also discussed, reviewing recent results that indicate signaling through these two receptor modalities leads to opposing cellular outcomes. We also provide an intriguing look into the transient receptor potential channel (TRPC) family of ion channels as distinctive targets of BDNF signaling; these channels are critical for capacitative Ca(2+) entry, which, in due course, mediates changes in neuronal structure including dendritic spine density. Finally, we expand these topics into an exploration of mental retardation (MR), in particular Rett Syndrome (RTT), where dendritic spine abnormalities may underlie cognitive impairments. We propose that understanding the role of neurotrophins in synapse formation, plasticity, and maintenance will make fundamental contributions to the development of therapeutic strategies to improve cognitive function in developmental disorders associated with MR.
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PMID:Transient receptor potential channels as novel effectors of brain-derived neurotrophic factor signaling: potential implications for Rett syndrome. 1711 56

Hereditary sensory and autonomic neuropathy type IV (HSAN IV) or congenital insensitivity to pain with anhidrosis (CIPA) is an autosomal-recessive disorder affecting the neurotrophin signal transduction pathway. HSAN IV is characterized by absence of reaction to noxious stimuli, recurrent episodes of fever, anhidrosis, self mutilating behaviour and frequent mental retardation. Mutations in the neurotrophic tyrosine kinase receptor type 1 (NTRK1) are associated with this disorder. We investigated NTRK1 mutations in five HSAN IV patients and one less typical patient with hypohidrosis, insensitivity to pain as well as motor- and sensory deficits in the peripheral nervous system. For the HSAN IV patients we identified a homozygous missense mutation (p.I572S), a homozygous deletion of 1985bp (g.7335164-7336545del), a homozygous insertion c.722_723insC in exon 7 and two compound heterozygous mutations (p.Q558X+p.L717R). The less typical patient as well as one HSAN IV patient revealed no NTRK1 mutation.
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PMID:Novel missense, insertion and deletion mutations in the neurotrophic tyrosine kinase receptor type 1 gene (NTRK1) associated with congenital insensitivity to pain with anhidrosis. 1807 66

The process of axonal and dendritic development establishes the synaptic circuitry of the central nervous system (CNS) and is the result of interactions between intrinsic molecular factors and the external environment. One growth factor that has a compelling function in neuronal development is the neurotrophin brain-derived neurotrophic factor (BDNF). BDNF participates in axonal and dendritic differentiation during embryonic stages of neuronal development, as well as in the formation and maturation of dendritic spines during postnatal development. Recent studies have also implicated vesicular trafficking of BDNF via secretory vesicles, and both secretory and endosomal trafficking of vesicles containing synaptic proteins, such as neurotransmitter and neurotrophin receptors, in the regulation of axonal and dendritic differentiation, and in dendritic spine morphogenesis. Several genes that are either mutated or deregulated in neurodevelopmental disorders associated with mental retardation have now been identified, and several mouse models of these disorders have been generated and characterized. Interestingly, abnormalities in dendritic and synaptic structure are consistently observed in human neurodevelopmental disorders associated with mental retardation, and in mouse models of these disorders as well. Abnormalities in dendritic and synaptic differentiation are thought to underlie altered synaptic function and network connectivity, thus contributing to the clinical outcome. Here, we review the roles of BDNF and vesicular trafficking in axonal and dendritic differentiation in the context of dendritic and axonal morphological impairments commonly observed in neurodevelopmental disorders associated with mental retardation.
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PMID:Modulation of dendritic spine development and plasticity by BDNF and vesicular trafficking: fundamental roles in neurodevelopmental disorders associated with mental retardation and autism. 1996 31


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