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)

Angelman syndrome (AS), characterized by mental retardation, seizures, frequent smiling and laughter, and abnormal gait, is one of the best examples of human disease in which genetic imprinting plays a role. In about 70% of cases, AS is caused by de novo maternal deletions at 15q11-q13 (ref. 2). Approximately 2% of AS cases are caused by paternal uniparental disomy (UPD) of chromosome 15 (ref. 3) and 2-3% are caused by "imprinting mutations'. In the remaining 25% of AS cases, no deletion, uniparental disomy (UPD), or methylation abnormality is detectable, and these cases, unlike deletions or UPD, can be familial. These cases are likely to result from mutations in a gene that is expressed either exclusively or preferentially from the maternal chromosome 15. We have found that a 15q inversion inherited by an AS child from her normal mother disrupts the 5' end of the UBE3A (E6-AP) gene, the product of which functions in protein ubiquitination. We have looked for novel UBE3A mutations in nondeletion/non-UPD/non-imprinting mutation (NDUI) AS patients and have found one patient who is heterozygous for a 5-bp de novo tandem duplication. We have also found in two brothers a heterozygous mutation, an A to G transition that creates a new 3' splice junction 7 bp upstream from the normal splice junction. Both mutations are predicted to cause a frameshift and premature termination of translation. Our results demonstrate that UBE3A mutations are one cause of AS and indicate a possible abnormality in ubiquitin-mediated protein degradation during brain development in this disease.
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PMID:UBE3A/E6-AP mutations cause Angelman syndrome. 898 71

Angelman syndrome (AS), characterized by motor dysfunction, mental retardation, and seizures, is caused by several genetic etiologies involving chromosome 15q11-q13, including mutations of the UBE3A gene. UBE3A encodes UBE3A/E6-AP, a ubiquitin-protein ligase, and shows brain-specific imprinting, with brain expression predominantly from the maternal allele. Lack of a functional maternal allele of UBE3A causes AS. In order to understand the causal relationship between maternal UBE3A mutations and AS, we have constructed a mouse model with targeted inactivation of Ube3a. The inactive allele contains a lacZ reporter gene for analysis of brain-specific imprinting. Maternal, but not paternal, transmission of the targeted allele leads to beta-galactosidase activity in hippocampal and cerebellar neurons. Maternal inheritance of the Ube3a mutant allele also causes impaired performance in tests of motor function and spatial learning, as well as abnormal hippocampal EEG recordings. As predicted from the dependence of UBE3A-mediated ubiquitination of p53 on HPV E6 protein, our maternal-deficient mice show normal brain p53 levels.
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PMID:Neurobehavioral and electroencephalographic abnormalities in Ube3a maternal-deficient mice. 1189 68

Angelman syndrome (AS) is a neurobehavioral disorder associated with mental retardation, absence of language development, characteristic electroencephalography (EEG) abnormalities and epilepsy, happy disposition, movement or balance disorders, and autistic behaviors. The molecular defects underlying AS are heterogeneous, including large maternal deletions of chromosome 15q11-q13 (70%), paternal uniparental disomy (UPD) of chromosome 15 (5%), imprinting mutations (rare), and mutations in the E6-AP ubiquitin ligase gene UBE3A (15%). Although patients with UBE3A mutations have a wide spectrum of neurological phenotypes, their features are usually milder than AS patients with deletions of 15q11-q13. Using a chromosomal engineering strategy, we generated mutant mice with a 1.6-Mb chromosomal deletion from Ube3a to Gabrb3, which inactivated the Ube3a and Gabrb3 genes and deleted the Atp10a gene. Homozygous deletion mutant mice died in the perinatal period due to a cleft palate resulting from the null mutation in Gabrb3 gene. Mice with a maternal deletion (m-/p+) were viable and did not have any obvious developmental defects. Expression analysis of the maternal and paternal deletion mice confirmed that the Ube3a gene is maternally expressed in brain, and showed that the Atp10a and Gabrb3 genes are biallelically expressed in all brain sub-regions studied. Maternal (m-/p+), but not paternal (m+/p-), deletion mice had increased spontaneous seizure activity and abnormal EEG. Extensive behavioral analyses revealed significant impairment in motor function, learning and memory tasks, and anxiety-related measures assayed in the light-dark box in maternal deletion but not paternal deletion mice. Ultrasonic vocalization (USV) recording in newborns revealed that maternal deletion pups emitted significantly more USVs than wild-type littermates. The increased USV in maternal deletion mice suggests abnormal signaling behavior between mothers and pups that may reflect abnormal communication behaviors in human AS patients. Thus, mutant mice with a maternal deletion from Ube3a to Gabrb3 provide an AS mouse model that is molecularly more similar to the contiguous gene deletion form of AS in humans than mice with Ube3a mutation alone. These mice will be valuable for future comparative studies to mice with maternal deficiency of Ube3a alone.
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PMID:Altered ultrasonic vocalization and impaired learning and memory in Angelman syndrome mouse model with a large maternal deletion from Ube3a to Gabrb3. 2080 28

Angelman syndrome (AS) is a neurodevelopmental disorder characterized by mental retardation and impaired speech. Because patients with this disorder often exhibit motor tremor and stereotypical behaviors, which are associated with basal ganglia pathology, we hypothesized that AS is accompanied by abnormal functioning of the striatum, the input nucleus of the basal ganglia. Using mutant mice with maternal deficiency of AS E6-AP ubiquitin protein ligase Ube3a (Ube3a(m-/p+) ), we assessed the effects of Ube3a deficiency on instrumental conditioning, a striatum-dependent task. We used whole-cell patch-clamp recording to measure glutamatergic transmission in the dorsomedial striatum (DMS) and dorsolateral striatum (DLS). Ube3a(m-/p+) mice were severely impaired in initial acquisition of lever pressing. Whereas the lever pressing of wild-type controls was reduced by outcome devaluation and instrumental contingency reversal, the performance of Ube3a(m-/p+) mice were more habitual, impervious to changes in outcome value and action-outcome contingency. In the DMS, but not the DLS, Ube3a(m-/p+) mice showed reduced amplitude and frequency of miniature excitatory postsynaptic currents. These results show for the first time a selective deficit in instrumental conditioning in the Ube3a deficient mouse model, and suggest a specific impairment in glutmatergic transmission in the associative corticostriatal circuit in AS.
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PMID:Region-specific impairments in striatal synaptic transmission and impaired instrumental learning in a mouse model of Angelman syndrome. 2432 62

The development of neurons is precisely controlled. Nerve cells are born from progenitor cells, migrate to their future target sites, extend dendrites and an axon to form synapses, and thus establish neural networks. All these processes are governed by multiple intracellular signaling cascades, among which ubiquitylation has emerged as a potent regulatory principle that determines protein function and turnover. Dysfunctions of E3 ubiquitin ligases or aberrant ubiquitin signaling contribute to a variety of brain disorders like X-linked mental retardation, schizophrenia, autism or Parkinson's disease. In this review, we summarize recent findings about molecular pathways that involve E3 ligases of the Homologous to E6-AP C-terminus (HECT) family and that control neuritogenesis, neuronal polarity formation, and synaptic transmission.
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PMID:HECT-type E3 ubiquitin ligases in nerve cell development and synapse physiology. 2597 71