Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0917816 (mental retardation)
 15,867 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mucopolysaccharidoses (MPS) are a family of lysosomal storage diseases resulting in developmental defects and, in some types, mental retardation and other neurological symptoms. To gain insight into the neurological dysfunction in MPS, we examined the morphology of olfactory epithelia (OE) and physiology of olfactory receptor neurons (ORNs) in cat models of MPS I, a type in which neuronal lesions are prominent, and MPS VI, in which they are essentially absent. Histopathology showed that both groups of MPS-affected cats had significantly thinner OE than controls. Although immature and mature ORNs were present in both MPS I and VI affected OE, the OE of MPS I-affected cats was structurally disorganized. ORN function was assessed with calcium imaging and patch-clamp recording. Few viable ORNs were recovered from MPS VI cats, but these exhibited normal responses to odors and pharmacological stimuli. In contrast, viable ORNs were as prevalent in MPS I as in controls but were significantly less likely to respond to odor stimuli, although other responses were normal. Disrupted OE organization and impaired ORN function in MPS I, but not MPS VI, corresponds to the central nervous system lesions found in MPS I but not MPS VI. These data represent the first neurophysiological correlate of this correspondence and have implications both for understanding the role of glycosaminoglycans in maintenance of the OE and for targeting further research into the basis for and treatment of the neurological consequences of MPS disorders.
 ...
PMID:Altered olfactory epithelial structure and function in feline models of mucopolysaccharidoses I and VI. 1880 39

The loss of Fragile X mental retardation protein (FMRP) causes Fragile X syndrome, the most common inherited mental retardation and single gene cause of autism. Although postsynaptic functions for FMRP are well established, potential roles at the presynaptic apparatus remain largely unexplored. Here, we characterize the expression of FMRP and its homologs, FXR1P and FXR2P, in the developing, mature and regenerating rodent nervous system, with a focus on presynaptic expression. As expected, FMRP is expressed in the somatodendritic domain in virtually all neurons. However, FMRP is also localized in discrete granules (Fragile X granules; FXGs) in a subset of brain regions including frontal cortex, hippocampal area CA3 and olfactory bulb glomeruli. Immunoelectron microscopy shows that FMRP is localized at presynaptic terminals and in axons within these FXG-rich regions. With the exception of the olfactory bulb, FXGs are prominent only in the developing brain. Experiments in regenerating olfactory circuits indicate that peak FXG expression occurs 2-4 weeks after neurogenesis, a period that correlates with synapse formation and refinement. Virtually all FXGs contain FXR2P, while region-selective subsets harbor FMRP and/or FXR1P. Genetic studies show that FXR2P is essential for FXG expression, while FMRP regulates FXG number and developmental profile. These findings suggest that Fragile X proteins play a distinct, presynaptic role during discrete developmental epochs in defined circuits of the mammalian CNS. We propose that the neurological defects in Fragile X syndrome, including the autistic features, could be due in part to the loss of FMRP function in presynaptic compartments.
 ...
PMID:The FXG: a presynaptic fragile X granule expressed in a subset of developing brain circuits. 1919 98

Creatine (Cr) is required to maintain ATP levels in the brain. The transport of Cr across the blood-brain barrier and into neurones requires a specific creatine transporter (CRT). Mutations in the CRT gene (SLC6A8) result in a novel form of X-linked mental retardation, characterised by developmental delays, seizures and a complete absence of Cr from the brain. To identify cell types and regions that depend on Cr for energy metabolism we have determined the regional and cellular localisation of CRT protein in the rat brain using immunohistochemical techniques with a highly specific, affinity-purified, CRT antibody. The results show high levels of CRT localisation is associated with specific brain regions and certain cell types. The CRT is predominantly found in neurones. CRT immunoreactivity is particularly abundant in the olfactory bulb, granule cells of the dentate gyrus of the hippocampus, pyramidal neurones of the cerebral cortex, Purkinje cells of the cerebellum, motor and sensory cranial nerve nuclei in the brainstem and the dorsal and ventral horns of the spinal cord. Low levels of CRT were seen in the basal ganglia and white matter. Overall, CRT was found to show high intensities of labelling in the major motor and sensory regions of the forebrain, brainstem and spinal cord and forebrain regions associated with learning, memory and limbic functions. It is hypothesised that regions with high CRT expression are likely to have high metabolic ATP requirements and that areas with low CRT levels are those regions which are particularly vulnerable in neurodegenerative diseases.
 ...
PMID:Immunohistochemical localisation of the creatine transporter in the rat brain. 1958 Aug 54

Autism susceptibility candidate 2 (Auts2) is a gene associated with autism and mental retardation, whose function is unknown. Expression of Auts2 mRNA and protein were studied in the developing mouse brain by in situ hybridization, immunohistochemistry, and western blotting. Auts2 mRNA was highly expressed in the developing cerebral cortex and cerebellum, regions often affected by neuropathological changes in autism, and a few other brain regions. On embryonic day (E) 12, Auts2 mRNA was expressed in the cortical preplate, where it colocalized with Tbr1, a transcription factor specific for postmitotic projection neurons. From E16 to postnatal day 21, Auts2 was expressed most abundantly in frontal cortex, hippocampus and cerebellum, including Purkinje cells and deep nuclei. High levels of Auts2 were also detected in developing dorsal thalamus, olfactory bulb, inferior colliculus and substantia nigra. Auts2 protein showed similar regional expression patterns as the mRNA. At the cellular level, Auts2 protein was localized in the nuclei of neurons and some neuronal progenitors.
 ...
PMID:Autism susceptibility candidate 2 (Auts2) encodes a nuclear protein expressed in developing brain regions implicated in autism neuropathology. 1994 50

The fragile X mental retardation protein (FMRP) is an RNA-binding protein essential for multiple aspects of neuronal mRNA metabolism. Its absence leads to the fragile X syndrome, the most prevalent genetic form of mental retardation. The anatomical landmark of the disease, also present in the Fmr1 knock-out (KO) mice, is the hyperabundance of immature-looking lengthened dendritic spines. We used the well known continuous production of adult-born granule cells (GCs) in the mouse olfactory bulb (OB) to analyze the consequences of Fmrp loss on the differentiation of GCs. Morphological analysis of GCs in the Fmr1 KO mice showed an increase in spine density without a change in spine length. We developed an RNA interference strategy to cell-autonomously mutate Fmr1 in a wild-type OB network. Mutated GCs displayed an increase in spine density and spine length. Detailed analysis of the spines through immunohistochemistry, electron microscopy, and electrophysiology surprisingly showed that, despite these abnormalities, spines receive normal glutamatergic synapses, and thus that mutated adult-born neurons are synaptically integrated into the OB circuitry. Time-course analysis of the spine defects showed that Fmrp cell-autonomously downregulates the level and rate of spine production and limits their overgrowth. Finally, we report that Fmrp does not regulate dendritogenesis in standard conditions but is necessary for activity-dependent dendritic remodeling. Overall, our study of Fmrp in the context of adult neurogenesis has enabled us to carry out a precise dissection of the role of Fmrp in neuronal differentiation and underscores its pleiotropic involvement in both spinogenesis and dendritogenesis.
 ...
PMID:Fragile X mental retardation protein regulates new neuron differentiation in the adult olfactory bulb. 2130 57

Symptoms like mental retardation, depression, and anxiety have been observed during aging. Almost similar phenotypes have been evident in patients having haploinsufficiency or mutations in Pax6, a transcriptional regulator. Since Pax6 regulates axon guidance, differentiation of neurons from glia, and neuronal migration, it has been considered as a marker of newly generated neurons. The immunohistochemical analysis of Pax6 positive cells and expression pattern of Pax6 in olfactory lobe, hippocampus, and cerebellum of aging mouse brain have been investigated. The number of Pax6 positive cells and level of Pax6 were reduced progressively in olfactory lobe, cerebellum, and hippocampus from postnatal day-zero (P0) to old age mice. Pax6 positive cells were significantly lower in dentate gyrus, CA1, CA2, and CA3 regions of hippocampus, in mitral cell (MiCe), and internal plexiform (InPl) layers of olfactory lobe, and in granular cell (GrLa), and Purkinje's cell (PuCe) layers of cerebellum from P0 to old age. Thus, modulation in the expression of Pax6 and reduction in Pax6 positive cells show direct association of Pax6 with aging-related neuronal dystrophy.
 ...
PMID:Aging-associated modulation in the expression of Pax6 in mouse brain. 2190 10

"Selective" or "picky eating" is a frequent problem in children with autism spectrum disorders (ASD). Many of these children do not treat sensory input, particularly olfactory, auditory, visual, and tactile information in the same manner as their typically developing peers of the same age. The purpose of this paper was to examine the relationship between problems of sensory processing and the number of eating problems in children with ASD. Of 95 children with ASD, 3 to 10 years of age, 65 percent showed a definite difference and 21 percent a probable difference in sensory processing on the total score of the Short Sensory Profile. These results were significantly related to an increase in the number of eating problems measured by the Eating Profile. These results could not be explained by age, sex, mental retardation, attention deficit disorder, or hyperactivity. Timely interventions focusing on the sensory components of eating must now be developed.
 ...
PMID:Association of sensory processing and eating problems in children with autism spectrum disorders. 2293 49

Gender plays a pivotal role in the human genetic identity and is also manifested in many genetic disorders particularly mental retardation. In this study its effect on copy number variation (CNV), known to cause genetic disorders was explored. As the olfactory receptor (OR) repertoire comprises the largest human gene family, it was selected for this study, which was carried out within and between three populations, derived from 150 individuals from the 1000 Genome Project. Analysis of 3872 CNVs detected among 791 OR loci, in which 307 loci showed CNV, revealed the following novel findings: Sex bias in CNV was significantly more prevalent in uncommon than common CNV variants of OR pseudogenes, in which the male genome showed more CNVs; and in one-copy number loss compared to complete deletion of OR pseudogenes; both findings implying a more recent evolutionary role for gender. Sex bias in copy number gain was also detected. Another novel finding was that the observed sex bias was largely dependent on ethnicity and was in general absent in East Asians. Using a CNV public database for sick children (International Standard Cytogenomic Array Consortium) the application of these findings for improving clinical molecular diagnostics is discussed by showing an example of sex bias in CNV among kids with autism. Additional clinical relevance is discussed, as the most polymorphic CNV-enriched OR cluster in the human genome, located on chr 15q11.2, is found near the Prader-Willi syndrome/Angelman syndrome bi-directionally imprinted region associated with two well-known mental retardation syndromes. As olfaction represents the primitive cognition in most mammals, arguably in competition with the development of a larger brain, the extensive retention of OR pseudogenes in females of this study, might point to a parent-of-origin indirect regulatory role for OR pseudogenes in the embryonic development of human brain. Thus any perturbation in the temporal regulation of olfactory system could lead to developmental delay disorders including mental retardation.
 ...
PMID:Sex bias in copy number variation of olfactory receptor gene family depends on ethnicity. 2350 16

We report the case of 3 brothers aged 34, 24, and 22 years, unmarried, who presented to our endocrinology clinic with absence of secondary sexual characters. There was no such history in other siblings, but their maternal uncle had similar complaints. On examination, all 3 had pre-pubertal appearance, voice, and genitalia along with anosmia and bimanual synkinesia. Cryptorchidism was noticed in 2 while third person had small hypoplastic testes. It was also noted that all 3 patients had icthyosis mainly involving trunk, back, and limbs. The hormonal assays were consistent with isolated hypogonadotrophic hypogonadism. IQ testing revealed mental retardation in the 2 patients. Ultrasound showed ectopic right kidney in one patient, atrophic right kidney in the second patient while the third patient had normal kidneys. MRI brain of all the patients showed poorly visualized olfactory tract and bulb. Kallmann syndrome (KS) was diagnosed based on hormonal evaluation and MRI results. Of the four types of KS: Synkinesia, renal anomaly, and X-linked pedigree pattern in our patients pointed towards X-linked type 1 KS as the possible cause. But, icthyosis and mental retardation are not usual presentation of type 1 KS. They are usually seen as a result of contiguous gene deletion of KAL1, steroid sulfatase (STS), and mental retardation (MRX) gene on X chromosome. Hence, the possible gene defect in our cases is inherited defect in contiguous gene deletion. The contiguous gene deletion as the cause of KS in 3 patients of same family is very rare and worth reporting. Also, the significance of phenotype-genotypic association in Kallmann syndrome is discussed.
 ...
PMID:Unusual presentation of Kallmannn syndrome with contiguous gene deletion in three siblings of a family. 2356 15

Fragile X mental retardation protein (FMRP) and Ataxin-2 (Atx2) are triplet expansion disease- and stress granule-associated proteins implicated in neuronal translational control and microRNA function. We show that Drosophila FMRP (dFMR1) is required for long-term olfactory habituation (LTH), a phenomenon dependent on Atx2-dependent potentiation of inhibitory transmission from local interneurons (LNs) to projection neurons (PNs) in the antennal lobe. dFMR1 is also required for LTH-associated depression of odor-evoked calcium transients in PNs. Strong transdominant genetic interactions among dFMR1, atx2, the deadbox helicase me31B, and argonaute1 (ago1) mutants, as well as coimmunoprecitation of dFMR1 with Atx2, indicate that dFMR1 and Atx2 function together in a microRNA-dependent process necessary for LTH. Consistently, PN or LN knockdown of dFMR1, Atx2, Me31B, or the miRNA-pathway protein GW182 increases expression of a Ca2+/calmodulin-dependent protein kinase II (CaMKII) translational reporter. Moreover, brain immunoprecipitates of dFMR1 and Atx2 proteins include CaMKII mRNA, indicating respective physical interactions with this mRNA. Because CaMKII is necessary for LTH, these data indicate that fragile X mental retardation protein and Atx2 act via at least one common target RNA for memory-associated long-term synaptic plasticity. The observed requirement in LNs and PNs supports an emerging view that both presynaptic and postsynaptic translation are necessary for long-term synaptic plasticity. However, whereas Atx2 is necessary for the integrity of dendritic and somatic Me31B-containing particles, dFmr1 is not. Together, these data indicate that dFmr1 and Atx2 function in long-term but not short-term memory, regulating translation of at least some common presynaptic and postsynaptic target mRNAs in the same cells.
...
PMID:FMRP and Ataxin-2 function together in long-term olfactory habituation and neuronal translational control. 2434 94


<< Previous 1 2 3 4 5 Next >>