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• W1966104820 abstract "The last 2–3 years have seen a series of exciting developments in the understanding of Angelman syndrome (AS), beginning with identification of the disease gene as a ubiquitin ligase gene (the first single-gene disorder of the ubiquitination pathway) and the demonstration of brain-specific imprinting for this gene. The imprinting center (IC) that regulates expression of genes in this region has been delineated, and a mouse model of the genetic defect has been characterized in detail, providing the first evidence for a mammalian gene that is required for long-term potentiation (LTP). AS is a neurologic disorder characterized by severe mental retardation, usually with the failure to learn speech; seizures that are accompanied by electroencephalogram abnormalities; a movement disorder, usually including gait ataxia and/or tremor of the hands; unusual behavior, including happy demeanor, frequent laughter, and easy excitability; delayed head growth with microcephaly by age 2 years; and sleep disturbance (Williams et al. Williams et al., 1995Williams CA Zori RT Hendrickson J Stalker H Marum T Whidden E Driscoll DJ Angelman syndrome.Curr Prob Pediatr. 1995; 25: 216-231PubMed Google Scholar). A summary of earlier observations with detailed bibliography (Ledbetter and Ballabio Ledbetter and Ballabio, 1995Ledbetter DH Ballabio A Molecular cytogenetics of contiguous gene syndromes: mechanisms and consequences of gene dosage imbalance.in: Scriver CR Beaudet AL Sly WS Valle D The metabolic and molecular bases of inherited disease. McGraw-Hill, New York1995: 811-839Google Scholar) and more-recent reviews of the molecular basis of AS are available (Lalande Lalande, 1996Lalande M Parental imprinting and human disease.Annu Rev Genet. 1996; 30: 173-195Crossref PubMed Scopus (135) Google Scholar; Jiang et al. Jiang et al., 1998bJiang Y Tsai T-F Bressler J Beaudet AL Imprinting in Angelman and Prader-Willi syndromes.Curr Opin Genet Dev. 1998b; 8: 334-342Crossref PubMed Scopus (98) Google Scholar; Nicholls et al. Nicholls et al., 1998Nicholls RD Saitoh S Horsthemke B Imprinting in Prader-Willi and Angelman syndromes.Trends Genet. 1998; 14: 194-200Abstract Full Text Full Text PDF PubMed Scopus (319) Google Scholar). Figure 1 depicts significant features of the AS and Prader-Willi syndrome (PWS) region of human chromosome 15q11-q13. A common interstitial ∼4-Mb deletion in this region is found in both AS and PWS, but the phenotypes in the two conditions are quite distinct, as is their pattern of inheritance: deletions on the paternal chromosome cause PWS, whereas those on the maternal chromosome cause AS. Consistent with this unusual parental effect, many but not all of the genes and transcripts from this region are subject to genomic imprinting. Thus, the SNRPN gene, encoding small nuclear ribonucleoprotein polypeptide N, is paternally expressed and maternally silenced in all tissues examined and represents an important landmark within the region. The SNRPN promoter is found within a CpG island that is completely methylated on the maternal chromosome and completely unmethylated on the paternal chromosome. A bipartite imprinting center overlaps this promoter; small deletions of the IC are implicated in imprinting defects that can lead to AS or PWS. Other notable loci in this region include the paternally expressed IPW, ZNF127, and NECDIN genes; the imprinting of UBE3A is tissue-specific, with maternal deficiency causing AS, and the imprinting status is uncertain for a cluster of GABAA receptor genes. The albinism locus (P) is not subject to genomic imprinting; the HECR2 gene, which encodes a highly conserved giant protein, and MN7 map near the common PWS/AS deletion breakpoints. AS is estimated to occur in 1/15,000 births, and the genetic basis for the disorder is unusually complex (table 1). A great majority of patients (65%–75%), designated type Ia in table 1, carry de novo interstitial deletions of maternal chromosome 15q11-q13. These deletions are thought to occur through unequal crossing over between complete or truncated copies of the HERC2 gene, which form a set of low-copy repeats (Ji et al. Ji et al., 1999Ji Y Walkowicz MJ Buiting K Johnson DK Tarvin RE Rinchik EM Horsthemke B et al.The ancestral gene for transcribed, low-copy repeats in the Prader-Willi/Angelman region encodes a large protein implicated in protein trafficking, which is deficient in mice with neuromuscular and spermiogenic abnormalities.Hum Mol Genet. 1999; 8: 533-542Crossref PubMed Scopus (95) Google Scholar). The common deletion is readily diagnosed by use of FISH, and its parental origin can be determined by methylation analysis; in maternal deletions, characteristic of AS of this type, the differentially methylated CpG island encompassing the promoter for SNRPN shows only the paternal, unmethylated pattern. Recurrence risk for this group of patients is extremely low. Closely related to this common deletion is a group of very rare mutations (<1%) including unbalanced translocations or inherited interstitial deletions (type Ib in table 1). For example, a Japanese family with an interstitial deletion that caused AS when inherited maternally, but that yielded a normal phenotype with no signs of Prader-Willi syndrome (PWS) when inherited paternally, was extremely valuable in distinguishing the critical regions for AS and PWS.Table 1Angelman SyndromeTypeMechanismProportionMethylationa“Abnormal” indicates that only the paternal, unmethylated pattern is seen on analysis of the SNRPN promoter region.RecurrenceIa∼4-Mb interstitial maternal del15q11-q1365%–75%AbnormalExtremely lowIbUnbalanced translocation or inherited interstitial deletion<1%Normal or abnormalSignificantIIaUPD maternal deficiency with normal parental chromosomes3%–5%AbnormalExtremely lowIIbUPD with predisposing parental translocation<1%AbnormalSignificantIIIaImprinting mutation with deletion of IC3%–5%AbnormalSignificantIIIbImprinting mutation without detectable deletion of IC3%–5%AbnormalLowIVPoint mutations in UBE3A4%–6%NormalSignificantVAS phenotype with no identifiable molecular abnormality10%–14%NormalOccurs rarelya “Abnormal” indicates that only the paternal, unmethylated pattern is seen on analysis of the SNRPN promoter region. Open table in a new tab Approximately 3%–5% of patients with AS have paternal uniparental disomy (UPD) with maternal deficiency for 15q11-q13 and normal parental chromosomes (type IIa). Recurrence risk is low for UPD unless a parental translocation (type IIb) predisposes the family to recurrence. Approximately 7%–9% of patients with AS have “imprinting” mutations, in which the maternal chromosome has a paternal pattern of methylation and imprinted gene expression for 15q11-q13. Among the imprinting mutations, about half (type IIIa) are associated with small deletions that affect the more centromeric portion of the bipartite IC near the SNRPN promoter and that make the chromosome unable to switch from the paternal to the maternal pattern of methylation and expression; most cases of AS type IIIa are familial (Ohta et al. Ohta et al., 1999Ohta T Buiting K Kokkonen H McCandless S Heeger S Leisti H Driscoll DJ et al.Molecular mechanism of Angelman syndrome in two large families involves an imprinting mutation.Am J Hum Genet. 1999; 64: 385-396Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar). Other cases that are identified as imprinting mutations on the basis of methylation analysis are not associated with detectable deletions in the IC (type IIIb). Familial recurrence has not been reported for this group of patients, and the molecular mechanism causing their defective imprinting mutation is unknown (Buiting et al. Buiting et al., 1998Buiting K Dittrich B Groß S Lich C Buchholz T Smith E Reis A et al.Sporadic imprinting defects in Prader-Willi syndrome and Angelman syndrome: implications for imprint-switch models, genetic counseling, and prenatal diagnosis.Am J Hum Genet. 1998; 63: 170-180Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar). The UBE3A gene, which encodes E6-AP ubiquitin-protein ligase (also known as ubiquitin ligase 3A) was mapped to the AS critical region in 1994, but it was not initially considered a strong candidate as an AS gene because it did not appear to be imprinted. Subsequently, however, point mutations in UBE3A, mostly truncating mutations, were found in a significant but relatively small fraction (4%–6%), of patients with AS (type IV). Some of these mutations occurred de novo, but many were inherited, and some families in this group include a large number of affected individuals (Malzac et al. Malzac et al., 1998Malzac P Webber H Moncla A Graham JM Kukolich M Williams C Pagon RA et al.Mutation analysis of UBE3A in Angelman syndrome patients.Am J Hum Genet. 1998; 62: 1353-1360Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar; Fang et al. Fang et al., 1999Fang P Lev-Lehman E Tsai T-F Matsuura T Benton CS Sutcliffe JS Christian SL et al.The spectrum of mutations in UBE3A causing Angelman syndrome.Hum Mol Genet. 1999; 8: 129-135Crossref PubMed Scopus (123) Google Scholar). When large numbers of type IIIa or type IV AS cases occur in an extended family, the pattern of inheritance is distinctive, in that heterozygotes are normal if the mutant chromosome is inherited from the father but are affected if it is inherited from the mother. The patients with point mutations in UBE3A encoding E6-AP have relatively typical and complete AS phenotypes (see Modifier Effects section, below). A final group of patients (10%–14%) with a clinical diagnosis of AS have no identifiable molecular abnormality (type V). This group of patients likely represents some combination of (1) as yet undetected lesions in chromosome 15q11-q13 that affect the UBE3A locus; (2) other novel genetic lesions that map elsewhere but affect expression of UBE3A; and (3) incorrect diagnoses, representing genocopies or phenocopies that do not perturb the expression of UBE3A. Because studies of patients with AS with normal methylation patterns have identified UBE3A mutations much more often in multiplex families than in isolated cases, it is likely that many patients with type V are erroneously diagnosed with AS or that there is yet another molecular mechanism with low recurrence risk to be identified. In most cases, AS can be diagnosed and patients can be counseled adequately by use of a combination of FISH, methylation analysis, and DNA marker studies for UPD, but it is labor intensive to search thoroughly for IC deletions with imprinting mutations or for mutations in UBE3A. Because only a small fraction of patients with a normal methylation pattern have identifiable UBE3A mutations, the frequency of patients with all laboratory studies yielding normal results (type V) is significant, leaving clinicians and families with uncertain diagnosis and recurrence risk. The P locus is not imprinted, but it falls within the ∼4-Mb common deletion region and modifies the phenotype to include mild hypopigmentation in the type Ia deletion form of AS. In humans or mice with loss-of-function mutations on both alleles for the P or p loci, respectively, the phenotype is albinism. The heterozygote phenotype is more obvious in mice but is associated with a mild decrease in pigmentation in humans. Hypopigmentation is not thought to be part of the phenotype observed in type II, III, or IV AS, involving UPD, imprinting mutations, or point mutations in UBE3A, respectively. Most type IV patients with AS have epilepsy, but some reports suggest that epilepsy is more severe in patients with type Ia who carry the ∼4-Mb deletion. The difference may be related to the presence of a cluster of GABAA receptor genes located between UBE3A and the P locus, as suggested by the finding that a knockout mutation for one of these receptors (Gabrb3) causes epilepsy in mice (Delorey et al. Delorey et al., 1998Delorey TM Handforth A Anagnostaras SG Homanics GE Minassian BA Asatourian A Fanselow MS et al.Mice lacking the β3 subunit of the GABAA receptor have the epilepsy phenotype and many of the behavioral characteristics of Angelman syndrome.J Neurosci. 1998; 18: 8505-8514Crossref PubMed Google Scholar). The status of genomic imprinting regarding the GABAA cluster of receptors is uncertain (see bibliography in Jiang et al. Jiang et al., 1998bJiang Y Tsai T-F Bressler J Beaudet AL Imprinting in Angelman and Prader-Willi syndromes.Curr Opin Genet Dev. 1998b; 8: 334-342Crossref PubMed Scopus (98) Google Scholar), but maternal deficiency for GABRB3 may function as a modifier of the epilepsy phenotype, accounting for the possibly greater severity in the deletion cases. Thus, type IV AS is a single-gene disorder with point mutations in UBE3A, but type Ia AS represents a contiguous gene syndrome, in which UBE3A, P, and perhaps GABRB3 all contribute to the phenotype. Despite the complexity of AS inheritance, the major phenotypic effects derive in all cases from deficient expression or function of the maternal UBE3A allele. Although imprinted expression was not found for UBE3A in cultured human cells, once mutations causing AS were found, it was quickly discovered that UBE3A is imprinted in human brain and that the paternal allele is silenced in that organ (Rougeulle et al. Rougeulle et al., 1997Rougeulle C Glatt H Lalande M The Angelman syndrome candidate gene, UBE3A/E6-AP, is imprinted in brain.Nat Genet. 1997; 17: 14-15Crossref PubMed Scopus (310) Google Scholar; Vu and Hoffman Vu and Hoffman, 1997Vu TH Hoffman AR Imprinting of the Angelman syndrome gene, UBE3A, is restricted to brain.Nat Genet. 1997; 17: 12-13Crossref PubMed Scopus (230) Google Scholar). More-detailed in situ hybridization data from the mouse indicates that Ube3a is preferentially expressed from the maternal allele with silencing of the paternal allele in Purkinje cells, hippocampal neurons, and olfactory mitral cells, whereas expression is not imprinted in most parts of the brain or in other somatic tissues. This tissue specificity was first described in UPD mice (Albrecht et al. Albrecht et al., 1997Albrecht U Sutcliffe JS Cattanach BM Beechey CV Armstrong D Eichele G Beaudet AL Imprinted expression of the murine Angelman syndrome gene, Ube3a, in hippocampal and Purkinje neurons.Nat Genet. 1997; 17: 75-78Crossref PubMed Scopus (381) Google Scholar) and has been confirmed by use of a gene-targeting mutation (as described below; also see Jiang et al. Jiang et al., 1998aJiang Y Armstrong D Albrecht U Atkins CM Noebels JL Eichele G Sweatt JD et al.Mutation of the Angelman ubiquitin ligase in mice causes increased cytoplasmic p53 and deficits of contextual learning and long-term potentiation.Neuron. 1998a; 21: 799-811Abstract Full Text Full Text PDF PubMed Scopus (612) Google Scholar). The maternal deficiency of Ube3a in Purkinje cells in mice could account for the ataxia and tremor seen in patients with AS, and the deficiency in the hippocampal neurons may explain learning deficits and epilepsy, but the sublocalization of tissue-specific imprinting in the brain has yet to be determined in humans. As discussed below, indirect evidence, based on excessive cytoplasmic p53 in the AS brain, suggests that the gene is imprinted in human Purkinje cells. The molecular basis for the tissue-specific imprinting is unknown but may be similar to the mechanisms used at other imprinted loci or for X inactivation. UBE3A uses multiple promoters and is subject to complex alternative splicing of 5′ untranslated exons, and there is precedent for alternative promoters involved in tissue-specific imprinting of IGF2 (Vu and Hoffman Vu and Hoffman, 1994Vu TH Hoffman AR Promoter-specific imprinting of the human insulin-like growth factor-II gene.Nature. 1994; 371: 714-717Crossref PubMed Scopus (199) Google Scholar). Molecular lesions that affect control elements separated from the structural gene by as much as a megabase are known to cause AS. One cis element that has been mapped to a 1.15-kb region in the more centromeric portion of the bipartite IC (Ohta et al. Ohta et al., 1999Ohta T Buiting K Kokkonen H McCandless S Heeger S Leisti H Driscoll DJ et al.Molecular mechanism of Angelman syndrome in two large families involves an imprinting mutation.Am J Hum Genet. 1999; 64: 385-396Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar) is required for switching from paternal to maternal epigenotype. There could well be tissue-specific enhancers or locus control regions (Tanimoto et al. Tanimoto et al., 1999Tanimoto K Liu Q Bungert J Engel JD Effects of altered gene order or orientation of the locus control region of human β-globin gene expression in mice.Nature. 1999; 398: 344-348Crossref PubMed Scopus (143) Google Scholar) between the IC and UBE3A or even flanking either of these sites. Also potentially relevant to the mechanism of imprinting is the report of an antisense transcript for the 3′ untranslated region of UBE3A (Rougeulle et al. Rougeulle et al., 1998Rougeulle C Cardoso C Fontes M Colleaux L Lalande M An imprinted antisense RNA overlaps UBE3A and a second maternally expressed transcript.Nat Genet. 1998; 19: 15-16Crossref PubMed Scopus (228) Google Scholar). Although molecular lesions involving other putative cis-acting elements may occur, it is the paternal silencing of UBE3A that is tissue specific. Activation of maternal expression is not involved, because the maternal allele is expressed quite ubiquitously. The E6-AP protein, the product of the UBE3A gene, was initially identified because of its ability to interact with the E6 protein of human papillomavirus to promote the ubiquitination and degradation of p53 (Huibregtse et al. Huibregtse et al., 1991Huibregtse JM Scheffner M Howley PM A cellular protein mediates association of p53 with the E6 oncoprotein of human papillomavirus types 16 or 18.EMBO J. 1991; 10: 4129-4135Crossref PubMed Scopus (659) Google Scholar). Ubiquitination (reviewed in Hershko and Ciechanover Hershko and Ciechanover, 1998Hershko A Ciechanover A The ubiquitin system.Annu Rev Biochem. 1998; 67: 425-479Crossref PubMed Scopus (6470) Google Scholar) involves four different classes of proteins that act together to target selected proteins for degradation. An E1 enzyme begins the process by forming a high-energy thioester bond between a cysteine of its active site and the C-terminal amino acid of ubiquitin. Activated ubiquitin is then transferred to a series of E2 enzymes that also form thioester-linked complexes with ubiquitin. Ubiquitin is then covalently attached to a protein substrate directly from an E2 enzyme or is transferred to a ubiquitin protein ligase (E3), which, in turn, ubiquitinates the target protein. E3 proteins, including E6-AP (Scheffner et al. Scheffner et al., 1993Scheffner M Huibregtse JM Vierstra RD Howley PM The HPV-16 ET and E6-AP complex functions as a ubiquitin-protein ligase in the ubiquitination of p53.Cell. 1993; 75: 495-505Abstract Full Text PDF PubMed Scopus (1881) Google Scholar), provide specific recognition of substrate proteins. E6-AP is the founding member of the homologous to E6-AP C-terminal (hect) domain family of E3 proteins that now includes as many as 20 different hect family proteins. Three other families of E3 ligases have been described: E3 proteins designated anaphase-promoting complex (APC) are implicated in control of the cell cycle, as are members of the phosphoprotein-ubiquitin ligase family, referred to as the Skp1-cullin-F box-protein (SCF) family. Another group of E3s, the N-end rule family, recognize substrates based on a characteristic N-terminal sequence (Hershko and Ciechanover Hershko and Ciechanover, 1998Hershko A Ciechanover A The ubiquitin system.Annu Rev Biochem. 1998; 67: 425-479Crossref PubMed Scopus (6470) Google Scholar). A final class of ubiquitination factor, termed “E4” by Koegl et al. (Koegl et al., 1999Koegl M Hoppe T Schlenker S Ulrich HD Mayer TU Jentsch S A novel ubiquitination factor, E4, is involved in multiubiquitin chain assembly.Cell. 1999; 96: 635-644Abstract Full Text Full Text PDF PubMed Scopus (796) Google Scholar), was recently shown to allow target proteins to progress from the oligo-ubiquitinated state, which occurs by the action of hect domain-type E3 ligases, to multiubiquitination and proteosomal degradation. E6-AP can interact with and, presumably, accept ubiquitin from several E2 enzymes, including UbcH5, UbcH6, UbcH7, and UbcH8. Subsequently, E6-AP ubiquitinates at least four proteins, but its targets might easily number in the dozens or hundreds. In addition to p53, the targets include HHR23A, a protein homologous to the yeast DNA repair factor RAD23; MCM-7, a protein implicated in chromosomal replication; and E6-AP itself. In addition to its ubiquitination activity, E6-AP can also serve as a transcriptional coactivator for steroid hormone receptors (Nawaz et al. Nawaz et al., 1999Nawaz Z Lonard DM Smith CL Lev-Lehman E Tsai SY Tsai MJ O'Malley BW The Angelman syndrome-associated protein, E6-AP, is a coactivator for the nuclear hormone receptor superfamily.Mol Cell Biol. 1999; 19: 1182-1189Crossref PubMed Scopus (333) Google Scholar). Transcriptional regulation and ubiquitination appear to be independent activities, because an N-terminal domain appears to mediate the former activity, whereas the ubiquitination domain is located at the C-terminal portion of the protein. Mice with paternal UPD for chromosome 7 were first reported as a model for AS (Cattanach et al. Cattanach et al., 1997Cattanach BM Barr JA Beechey CV Martin J Noebels J Jones J A candidate model for Angelman syndrome in the mouse.Mamm Genome. 1997; 8: 472-478Crossref PubMed Scopus (73) Google Scholar), although a previously known radiation-induced deletion (p30Ub; Johnson et al. Johnson et al., 1995Johnson DK Stubbs LJ Culiat CT Montgomery CS Russell LB Rinchik EM Molecular analysis of 36 mutations at the mouse pink-eyed dilution (p) locus.Genetics. 1995; 141: 1563-1571PubMed Google Scholar) that lacks both the p locus and Ube3a could also be used to produce maternal deficiency for Ube3a. Both of these models involve large regions of mouse chromosome 7C and could affect multiple loci. We produced a null mutation in Ube3a by using gene targeting and found that maternal deficiency mice show no detectable expression of the locus in hippocampal neurons or in cerebellar Purkinje cells (Jiang et al. Jiang et al., 1998aJiang Y Armstrong D Albrecht U Atkins CM Noebels JL Eichele G Sweatt JD et al.Mutation of the Angelman ubiquitin ligase in mice causes increased cytoplasmic p53 and deficits of contextual learning and long-term potentiation.Neuron. 1998a; 21: 799-811Abstract Full Text Full Text PDF PubMed Scopus (612) Google Scholar). The maternal deficiency (AS) mice demonstrate motor dysfunction, inducible seizures, and a defect in contextual learning and hippocampal LTP. Contextual fear conditioning is an associative learning behavior implicated in rat brain–lesion studies to involve hippocampal function. LTP is an electrophysiological phenomenon whereby stimulation of presynaptic axons increases the strength of connections to postsynaptic neurons for days to weeks and is widely regarded as a form of neuronal plasticity that is relevant to learning and memory. LTP is generally considered the strongest candidate cellular mechanism for learning and memory (see Meiri et al. Meiri et al., 1998Meiri N Sun M-K Segal Z Alkon DL Memory and long-term potentiation (LTP) dissociated: normal spatial memory despite CA1 LTP elimination with Kv 1.4 antisense.Proc Natl Acad Sci USA. 1998; 95: 15037-15042Crossref PubMed Scopus (66) Google Scholar for a dissenting view; Stevens Stevens, 1998Stevens CF A million dollar question: Does LTP = memory?.Neuron. 1998; 20: 1-2Abstract Full Text Full Text PDF PubMed Scopus (129) Google Scholar). The defect in LTP, which is quite prominent in AS mice, represents the first evidence for a role of ubiquitination in mammalian LTP. In Aplysia, a much-studied model system for the molecular basis of associative learning, ubiquitin-dependent proteolysis is implicated in the synaptic changes that occur in long-term facilitation. Nevertheless, it is uncertain whether E6-AP plays a direct or indirect role in affecting LTP. Because the mice have normal neuroanatomy and normal baseline synaptic transmission (Jiang et al. Jiang et al., 1998aJiang Y Armstrong D Albrecht U Atkins CM Noebels JL Eichele G Sweatt JD et al.Mutation of the Angelman ubiquitin ligase in mice causes increased cytoplasmic p53 and deficits of contextual learning and long-term potentiation.Neuron. 1998a; 21: 799-811Abstract Full Text Full Text PDF PubMed Scopus (612) Google Scholar), the defect in LTP may represent a primary abnormality. AS mice have an increased abundance of cytoplasmic p53 in Purkinje cells and some hippocampal neurons, which suggests that E6-AP regulates the abundance of p53 directly in vivo through ubiquitination. Despite the flood of recent data on UBE3A expression and E6-AP biochemistry, the mechanisms whereby maternal deficiency of E6-AP causes the phenotypic features of AS remain largely unknown. Significant Purkinje cell and granule cell loss and increased abundance of p53 in Purkinje cells were found at autopsy in a 21-year-old patient with a clinical diagnosis of AS (Jay et al. Jay et al., 1991Jay V Becker LE Chan F-W Perry Sr, TL Puppet-like syndrome of Angelman: a pathologic and neurochemical study.Neurology. 1991; 41: 416-422Crossref PubMed Google Scholar; Jiang et al. Jiang et al., 1998aJiang Y Armstrong D Albrecht U Atkins CM Noebels JL Eichele G Sweatt JD et al.Mutation of the Angelman ubiquitin ligase in mice causes increased cytoplasmic p53 and deficits of contextual learning and long-term potentiation.Neuron. 1998a; 21: 799-811Abstract Full Text Full Text PDF PubMed Scopus (612) Google Scholar). However, normal neuropathology has been reported in a 3-year-old patient (Kyriakidas et al. Kyriakidas et al., 1992Kyriakidas T Hallam LA Hockey A Silberstein P Kakulas BA Angelman's syndrome: a neuropathological study.Acta Neuropathol (Berl). 1992; 83: 675-678Crossref PubMed Scopus (14) Google Scholar), which suggests that Purkinje cell death is, at most, a late effect of maternal deficiency for UBE3A. Moreover, the neuroanatomy in AS mice up to 3–4 mo of age is also normal, despite their phenotypic abnormalities. The elevated cytoplasmic levels of p53 in human Purkinje cells in AS suggest that expression of UBE3A is imprinted in this cell type in humans, as it is in mice. This high level of p53 might initiate apoptosis and contribute to cell loss at later ages. Candidate proteins in Purkinje cells and proteins implicated in LTP in the hippocampus can be evaluated as potential targets for ubiquitination by E6-AP. Ube3a mutant mice should provide an additional means to identify target proteins that are found in Purkinje cells or hippocampal neurons at elevated levels relative to wild type. Finally, the transcriptional coactivation capacity of E6-AP must be considered, along with ubiquitination, as possibly contributing to the pathogenesis. However, the finding that AS can arise from missense mutations in the ubiquitination domain may argue that ubiquitination defects per se are sufficient to cause the disease. The transcriptional function of some of these mutant E6-AP proteins appears to be preserved in tissue culture studies (Nawaz et al. Nawaz et al., 1999Nawaz Z Lonard DM Smith CL Lev-Lehman E Tsai SY Tsai MJ O'Malley BW The Angelman syndrome-associated protein, E6-AP, is a coactivator for the nuclear hormone receptor superfamily.Mol Cell Biol. 1999; 19: 1182-1189Crossref PubMed Scopus (333) Google Scholar). AS represents the first clear example of a single-gene disorder involving the ubiquitination pathway in humans, although numerous such defects have been described in yeast and Drosophila (see Jiang et al. Jiang et al., 1998aJiang Y Armstrong D Albrecht U Atkins CM Noebels JL Eichele G Sweatt JD et al.Mutation of the Angelman ubiquitin ligase in mice causes increased cytoplasmic p53 and deficits of contextual learning and long-term potentiation.Neuron. 1998a; 21: 799-811Abstract Full Text Full Text PDF PubMed Scopus (612) Google Scholar and references therein). In mice, the disruption of an E2 locus, UbcM4, leads to embryonic lethality (Harbers et al. Harbers et al., 1996Harbers K Li E Grams A Li E Jaenisch R Franz T Provirus integration into a gene encoding a ubiquitin-conjugating enzyme results in a placental defect and embryonic lethality.Proc Natl Acad Sci USA. 1996; 93: 12412-12417Crossref PubMed Scopus (56) Google Scholar), and a mutation in an E3 ubiquitin-protein ligase, encoded by the Itch locus, causes a complex spectrum of immunologic and inflammatory abnormalities (Perry et al. Perry et al., 1998Perry WL Hustad CM Swing DA O'Sullivan TN Jenkins NA Copeland NG The itchy locus encodes a novel ubiquitin protein ligase that is disrupted in a18H mice.Nat Genet. 1998; 18: 143-146Crossref PubMed Scopus (260) Google Scholar). The velocardiofacial/DiGeorge syndrome may be caused by a defect in a protein involved in degradation of ubiquitinated proteins (Yamagishi et al. Yamagishi et al., 1999Yamagishi H Garg V Matsuoka R Thomas T Srivastava D A molecular pathway revealing a genetic basis for human cardiac and craniofacial defects.Science. 1999; 283: 1158-1161Crossref PubMed Scopus (229) Google Scholar). Given the large number of E2 and E3 loci in mammals, it is likely that additional single-gene disorders involving the ubiquitination pathway will be identified in humans. In addition, abnormalities of ubiquitination are likely to be secondarily involved in many pathological conditions, and they are already implicated in neurodegenerative triple-repeat disorders (Cummings et al. Cummings et al., 1998Cummings CJ Mancini MA Antalffy B DeFranco DB Orr HT Zoghbi HY Chaperone suppression of aggregation and altered subcellular proteasome localization imply protein misfolding in SCA1.Nat Genet. 1998; 19: 148-154Crossref PubMed Scopus (733) Google Scholar; Chai et al. Chai et al., 1999Chai Y Koppenhafer SL Shoesmith SJ Perez MK Paulson HL Evidence for proteasome involvement in polyglutamine disease: localization to nuclear inclusions in SCA3/MJD and suppression of polyglutamine aggregation in vitro.Hum Mol Genet. 1999; 8: 673-682Crossref PubMed Scopus (338) Google Scholar), Alzheimer disease, and other neurodegenerative disorders (Alves-Rodrigues et al. Alves-Rodrigues et al., 1998Alves-Rodrigues A Gregori L Figueiredo-Pereira ME Ubiquitin, cellular inclusions and their role in neurodegeneration.Trends Neurosci. 1998; 21: 516-520Abstract Full Text Full Text PDF PubMed Scopus (332) Google Scholar). There is little precedent for the effects of abnormalities of LTP on human learning and behavior. Since mice with AS have an abnormality of LTP, it is of particular interest to carefully examine the cognitive features of human patients with AS. It is likely that additional instances will arise in which mice and humans carry mutations in orthologous genes and a defect in LTP will be shown in the mouse. Such models hold the promise of a deeper understanding of the relationships between the cellular events of LTP and the behavioral changes we observe as learning and memory in mice and humans. We apologize to the many authors whose primary data could not be cited because of limitations of space. We thank Grace Watson for great assistance in preparation of the manuscript. This work is supported by NIH grant HD 37283." @default.
• W1966104820 created "2016-06-24" @default.
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• W1966104820 date "1999-07-01" @default.
• W1966104820 modified "2023-09-27" @default.
• W1966104820 title "Genetics of Angelman Syndrome" @default.
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