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)

Fetal alcohol syndrome (FAS) stems from maternal alcohol abuse during pregnancy and is an important cause of mental retardation and hyperactivity in children. In the developing brain, alcohol can kill neurons, leading to microencephaly. However, due to their genetic makeup, some individuals are less vulnerable than others to alcohol's neurotoxic effects. Animal studies have demonstrated that one particular gene, neuronal nitric oxide synthase (nNOS), protects developing neurons in vivo against alcohol-induced death. We utilized pharmacologic techniques to demonstrate that nNOS protects neurons against alcohol toxicity by activating the NO-cGMP-PKG signaling pathway. Cerebellar granule cell cultures derived from mice carrying a null mutation for nNOS (nNOS-/- mice) were substantially more vulnerable than cultures from wild-type mice to alcohol-induced cell death. However, activation of the pathway at sites downstream of nNOS protected the cultures against alcohol toxicity. Conversely, blockade of the pathway rendered wild-type cultures vulnerable to alcohol-induced death. We further identified NF-kappaB as the downstream effector through which nNOS and the NO-cGMP-PKG pathway signal their neuroprotective effects. Tumor necrosis factor-alpha (TNF-alpha), which activates NF-kappaB, ameliorated alcohol-induced cell death in nNOS-/- and wild-type cultures, while an NF-kappaB inhibitor (NFi) blocked the protective effects of TNF-alpha and worsened alcohol-induced cell death. Furthermore, NFi blocked the protective effects of NO-cGMP-PKG pathway activators, demonstrating that NF-kappaB is downstream of the NO-cGMP-PKG pathway. As wild-type neurons matured in culture, they became resistant to alcohol toxicity. However, this maturation-dependent alcohol resistance did not occur in nNOS-/- mice and could be reversed in wild-type mice with NFi, demonstrating that nitric oxide and NF-kappaB are crucial for the development of alcohol resistance with age. Thus, nNOS protects developing neurons against alcohol toxicity by activating the NO-cGMP-PKG-NF-kappaB pathway and is crucial for the acquisition of maturation-dependent alcohol resistance.
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PMID:The protective effect of neuronal nitric oxide synthase (nNOS) against alcohol toxicity depends upon the NO-cGMP-PKG pathway and NF-kappaB. 1882 32

BACKGROUND Genome-wide screening of large patient cohorts with mental retardation using microarray-based comparative genomic hybridisation (array-CGH) has recently led to identification several novel microdeletion and microduplication syndromes. METHODS Owing to the national array-CGH network funded by the French Ministry of Health, shared information about patients with rare disease helped to define critical intervals and evaluate their gene content, and finally determine the phenotypic consequences of genomic array findings. RESULTS In this study, nine unrelated patients with overlapping de novo interstitial microdeletions involving 4q21 are reported. Several major features are common to all patients, including neonatal muscular hypotonia, severe psychomotor retardation, marked progressive growth restriction, distinctive facial features and absent or severely delayed speech. The boundaries and the sizes of the nine deletions are different, but an overlapping region of 1.37 Mb is defined; this region contains five RefSeq genes: PRKG2, RASGEF1B, HNRNPD, HNRPDL and ENOPH1. DISCUSSION Adding new individuals with similar clinical features and 4q21 deletion allowed us to reduce the critical genomic region encompassing two genes, PRKG2 and RASGEF1B. PRKG2 encodes cGMP-dependent protein kinase type II, which is expressed in brain and in cartilage. Information from genetically modified animal models is pertinent to the clinical phenotype. RASGEF1B is a guanine nucleotide exchange factor for Ras family proteins, and several members have been reported as key regulators of actin and microtubule dynamics during both dendrite and spine structural plasticity. CONCLUSION Clinical and molecular delineation of 4q21 deletion supports a novel microdeletion syndrome and suggests a major contribution of PRKG2 and RASGEF1B haploinsufficiency to the core phenotype.
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PMID:Microdeletion at chromosome 4q21 defines a new emerging syndrome with marked growth restriction, mental retardation and absent or severely delayed speech. 2052 26

When a mother abuses alcohol during pregnancy, the offspring can suffer a myriad of abnormalities, collectively known as fetal alcohol spectrum disorder (FASD). Foremost among these abnormalities is central nervous system dysfunction, which commonly manifests itself as mental retardation, clumsiness, hyperactivity, and poor attention span. These behavior problems are due, in large part, to alcohol-induced neuronal losses in the developing fetal brain. However, not all fetuses are equally affected by maternal alcohol consumption during pregnancy. While some fetuses are severely affected and develop hallmarks of FASD later in life, others exhibit no evident neuropathology or behavioral abnormalities. This variation is likely due, at least in part, to differences in fetal genetics. This review focuses on one particular gene, neuronal nitric oxide synthase, whose mutation worsens alcohol-induced neuronal death, both in vitro and in vivo. In addition, ectopic expression of the neuronal nitric oxide synthase gene protects neurons against alcohol toxicity. The gene encodes an enzyme that produces nitric oxide (NO), which facilitates the protective effects of neuronal growth factors and which underlies the ability of neurons to resist alcohol toxicity as they mature. Nitric oxide exerts its protective effects against alcohol via a specific signaling pathway, the NO-cGMP-PKG pathway. Pharmacologic manipulation of this pathway could be of therapeutic use in preventing or ameliorating FASD.
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PMID:The neuronal nitric oxide synthase (nNOS) gene and neuroprotection against alcohol toxicity. 2567 65