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)

In Down syndrome (DS), enhanced apoptosis (programmed cell death) may play a role in the pathogenesis of characteristic early mental retardation and precocious neurodegeneration of Alzheimer-type. The human IAP (inhibitor of apoptosis proteins) genes (NAIP, c-IAP-2/HIAP-1, c-IAP-1/Hiap-2, XIAP, survivin) are an evolutionary conserved family of proteins which prevent cell death across species, implying that they act at a central, highly conserved point in the cell death cascade. Evidence for downregulation of NAIP-mRNA in fetal DS (23rd week of gestation), as found by subtractive hybridization technique challenged studies at the protein level in adult DS brain specimen. NAIP-like immunoreactivity was determined in four different regions of cerebral cortex and cerebellum in 9 adult DS patients with Alzheimer-like neuropathologic lesions, 9 Alzheimer disease (AD) patients as compared to 9 controls. For the first time, NAIP-IR could be demonstrated in different cortical regions of the human brain. Compared to control subjects, western blotting demonstrated significantly decreased levels in parietal and occipital cortex in DS and in frontal and occipital cortex in AD. While the mode of NAIP action is unknown, inhibition of certain caspases has already been demonstrated for other IAP-family members (c-IAP1, c-IAP2 and XIAP). Although decreased NAIP-IR of certain brain regions in DS and AD awaits further confirmation, the results suggest that alterations of apoptosis regulatory (inhibitory) proteins may be another feature of neurodegeneration in DS and AD.
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PMID:Neuronal apoptosis inhibitory protein (NAIP)-like immunoreactivity in brains of adult patients with Down syndrome. 1066 83

Mental retardation (MR) is the most frequent handicap among children and young adults. Although a large proportion of X-linked MR genes have been identified, only four genes responsible for autosomal-recessive nonsyndromic MR (AR-NSMR) have been described so far. Here, we report on two genes involved in autosomal-recessive and X-linked NSMR. First, autozygosity mapping in two sibs born to first-cousin French parents led to the identification of a region on 8p22-p23.1. This interval encompasses the gene N33/TUSC3 encoding one subunit of the oligosaccharyltransferase (OTase) complex, which catalyzes the transfer of an oligosaccharide chain on nascent proteins, the key step of N-glycosylation. Sequencing N33/TUSC3 identified a 1 bp insertion, c.787_788insC, resulting in a premature stop codon, p.N263fsX300, and leading to mRNA decay. Surprisingly, glycosylation analyses of patient fibroblasts showed normal N-glycan synthesis and transfer, suggesting that normal N-glycosylation observed in patient fibroblasts may be due to functional compensation. Subsequently, screening of the X-linked N33/TUSC3 paralog, the IAP gene, identified a missense mutation (c.932T-->G, p.V311G) in a family with X-linked NSMR. Recent studies of fucosylation and polysialic-acid modification of neuronal cell-adhesion glycoproteins have shown the critical role of glycosylation in synaptic plasticity. However, our data provide the first demonstration that a defect in N-glycosylation can result in NSMR. Together, our results demonstrate that fine regulation of OTase activity is essential for normal cognitive-function development, providing therefore further insights to understand the pathophysiological bases of MR.
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PMID:Oligosaccharyltransferase-subunit mutations in nonsyndromic mental retardation. 1845 29

N-linked glycosylation is one of the most abundant modifications of proteins in eukaryotic organisms. In the central reaction of the pathway, oligosaccharyltransferase (OST), a multimeric complex located at the membrane of the endoplasmic reticulum, transfers a preassembled oligosaccharide to selected asparagine residues within the consensus sequence asparagine-X-serine/threonine. Due to the high substrate specificity of OST, alterations in the biosynthesis of the oligosaccharide substrate result in the hypoglycosylation of many different proteins and a multitude of symptoms observed in the family of congenital disorders of glycosylation (CDG) type I. This review covers our knowledge of human OST and describes enzyme composition. The Stt3 subunit of OST harbors the catalytic center of the enzyme, but the function of the other, highly conserved, subunits are less well defined. Some components seem to be involved in the recognition and utilization of glycosylation sites in specific glycoproteins. Indeed, mutations in the subunit paralogs N33/Tusc3 and IAP do not yield the pleiotropic phenotypes typical for CDG type I but specifically result in nonsyndromic mental retardation, suggesting that the oxidoreductase activity of these subunits is required for glycosylation of a subset of proteins essential for brain development.
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PMID:Oligosaccharyltransferase: the central enzyme of N-linked protein glycosylation. 2161 85

Congenital disorders of glycosylation (CDG) are genetic diseases due to defects in the synthesis or the attachment of the glycan moiety of glycoproteins and glycolipids. They can be divided into four groups: disorders of protein N-glycosylation, disorders of protein O-glycosylation, disorders of lipid glycosylation, and disorders of other glycosylation pathways and of multiple glycosylation pathways. Of the more than 40 reported CDG, some 80% are neurological or have an important neurological component. By far the most common neurological CDG is phosphomannomutase 2 deficiency. Isoelectrofocusing of serum transferrin, the most widely used screening test, picks up only CDG associated with sialic acid deficiency of N-linked glycans. Predominant neurological signs and symptoms are psychomotor retardation, epilepsy, hypotonia, hyporeflexia, strabismus, retinitis pigmentosa, polyneuropathy, myopathy, and cerebellar hypotrophy/hypoplasia. All known neurological CDG have an autosomal recessive inheritance except for IAP-CDG, an X-linked pure mental retardation syndrome. No curative or effective treatment is available for neurological CDG. Since at least 1% of the genome is involved in glycosylation, it is likely that the large majority of CDG is yet to be discovered. In 2008, a novel nomenclature was introduced using the gene symbol followed by -CDG, e.g., CDG-Ia becomes PMM2-CDG. CDG should be looked for in any unexplained neurological syndrome.
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PMID:Congenital disorders of glycosylation. 2362 97