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)

An understanding of brain development and brain function at the level of the genome is developing rapidly, because of the availability of new technologies in molecular and cellular biology. This understanding can be further enhanced by an interactive exchange between the disciplines of behavioural neuroscience and molecular genetics. New genes are being cloned almost daily, but their function remains an enigma. The purpose of this review is to illustrate how reporter genes can be used to map the brain's genetic activity in developmental time and anatomical space. The production of mutants in the homozygous condition may further lead to a morphological or behavioural phenotype. A knowledge of behavioural neuroscience can provide a prescreen of the reporter distribution and thereby make predictions concerning the type of behavioural analysis required. This approach allows selective cloning and sequencing of those genes which have either a morphological or behavioural phenotype but are transcribed at low levels. It is known that genomic imprinting influences brain development, and also that human genetic mutations and deletions influence imprinting in mental retardation as well as certain behavioural disorders. Precisely how such imprinted genes influence brain development and behaviour is being pursued by the use of chimeras. The distribution of maternal or paternal disomy cells in the brain and the way they influence behaviour may reveal the phenotype and how this is brought about.
 ...
PMID:Molecular genetic approaches to understanding brain development and behaviour. 793 42

Many newborns who appear normal at birth later manifest substantial neurologic and other disease. Pathologists are able to explain some of that sad enigma. Placental pathology frequently reveals the pathogenesis of cerebral palsy, mental retardation, and other neurodevelopmental disorders. This requires recognition of gross placental abnormalities and insightful light microscopic examination. Chorioamnionitis is now proven to be the major cause of premature onset of labor and prematurity. There is important need for investigation of pathogenetic processes associated with ascending intrauterine infection. Major complications therein include bacterially mediated fetal hypoperfusion resulting from placental and umbilical vasocontraction. Placentas of 10% of newborns have villitis of unknown etiology. The importance of villitis is incompletely known. The fetus may discharge meconium on more than one occasion, particularly so when the fetus is postmature. Clinicians may not recognize that fetal discharge has occurred if the event occurred 4 days or more prior to delivery. Intra-amniotic meconium associated with oligohydramnios probably causes placental and umbilical vasocontraction. Meconium probably thus contributes to the pathogenesis of pulmonary vasoconstriction, persistent fetal circulation, necrotizing enterocolitis, and damage of the fetal brain, liver, and kidneys. Fetal hypoxia and asphyxia may be acutely or chronically acquired. Major placental lesions associated with neonatal asphyxia include chronic ischemic change, nucleated red blood cells, intravillous hemorrhages, intimal vascular fibrin cushions, meconium staining, and intervillous fibrin.
 ...
PMID:Some placental considerations related to neurodevelopmental and other disorders. 844 76

Aneuploidy is one of the most common and serious pregnancy complications in humans. Most conceptuses with autosomal aneuploidy die in utero, resulting in early pregnancy loss. However, some fetuses with aneuploidy survive to term but suffer from disorders associated with congenital anomalies and mental retardation, such as Down syndrome with trisomy 21. Three general characteristics of this condition are well acknowledged: (i) in most cases the extra chromosome is of maternal origin; (ii) most cases are derived from a malsegregation event in meiosis I; and (iii) the frequency of these errors increases with maternal age. The basis for the age-dependent increase in meiosis I errors has been a long-standing enigma. Many investigators have addressed the nature of this biological phenomenon through genomic analyses of extra chromosome 21 using polymorphic markers to determine the frequency or location of crossovers that should ensure faithful chromosome segregation. Cytogenetic analyses of in vitro unfertilized oocytes have also been performed. However, no definitive conclusions regarding meiosis I errors have yet been reached from such studies. Recent findings in conditional knock-out mice for meiosis-specific cohesin have shed further light on this issue. The present review focuses on the current understanding of age-related aneuploidy and provides an overview of the mechanisms involved. We refer to recent data to illustrate some of the new paradigms that have arisen in this field.
 ...
PMID:Molecular basis of maternal age-related increase in oocyte aneuploidy. 2234 79

P4-ATPases (flippases) translocate specific phospholipids such as phosphatidylserine from the exoplasmic leaflet of the cell membrane to the cytosolic leaflet, upholding an essential membrane asymmetry. The mechanism of flipping this giant substrate has remained an enigma. We have investigated the importance of amino acid residues in transmembrane segment M4 of mammalian P4-ATPase ATP8A2 by mutagenesis. In the related ion pumps Na(+),K(+)-ATPase and Ca(2+)-ATPase, M4 moves during the enzyme cycle, carrying along the ion bound to a glutamate. In ATP8A2, the corresponding residue is an isoleucine, which recently was found mutated in patients with cerebellar ataxia, mental retardation, and dysequilibrium syndrome. Our analyses of the lipid substrate concentration dependence of the overall and partial reactions of the enzyme cycle in mutants indicate that, during the transport across the membrane, the phosphatidylserine head group passes near isoleucine-364 (I364) and that I364 is critical to the release of the transported lipid into the cytosolic leaflet. Another M4 residue, N359, is involved in recognition of the lipid substrate on the exoplasmic side. Our functional studies are supported by structural homology modeling and molecular dynamics simulations, suggesting that I364 and adjacent hydrophobic residues function as a hydrophobic gate that separates the entry and exit sites of the lipid and directs sequential formation and annihilation of water-filled cavities, thereby enabling transport of the hydrophilic phospholipid head group in a groove outlined by the transmembrane segments M1, M2, M4, and M6, with the hydrocarbon chains following passively, still in the membrane lipid phase.
...
PMID:Critical roles of isoleucine-364 and adjacent residues in a hydrophobic gate control of phospholipid transport by the mammalian P4-ATPase ATP8A2. 2470 22

Toxocara canis belongs to one of zoonotic parasites that commonly infects canines worldwide, and its eggs in host faeces may contaminate the food, water, soil and their fur as well as the larvae entrapped in the granuloma can infect paratenic hosts including mice and humans. Survivability of T. canis embryonated eggs under moist, cool conditions may be as long as 2-4 years or more. In paratenic hosts such as mice and humans, T. canis L3 larvae neither moult, grow, nor replicate and will wander through a number of internal organs in humans so as to cause Th2-dominant pathology in various internal organs as leading to neurotoxocariasis (NT), ocular toxocariasis (OT), or visceral larva migrans (VLM). Although the systemic immune response to T. canis has been widely reported, the immune response in the brain has received little attention. Differential cytokine expression and other brain injury-associated biomarkers or neurodegeneration-associated factors have been observed in infected versus uninfected outbred and inbred mice. Preliminary data have also suggested a possible link between significant memory impairment and cytokine production associated with T. canis infection in the hippocampus which has been long recognised as being responsible for learning and memory functions. Notably, it remains an enigma concerning cerebral invasion by T. canis larvae rarely induces a recognisable neurological syndrome or its involvement in neuropathological disorders in humans. Exploration of the relationship between host and parasite in the brain may elucidate the cryptic symptoms of human cerebral toxocariasis, with patients presenting with mental retardation, epilepsy, neurodegeneration and other central nervous system (CNS) disorders.
 ...
PMID:Pathogenesis of cerebral toxocariasis and neurodegenerative diseases. 3238 Dec