Angelman syndrome: a review of clinical and genetic aspects

Laan, L.A.E.M.; Haeringen, Arie van; Brouwer, Oebele F.

doi:10.1016/s0303-8467(99)00030-x

Cited by 75 publications

(59 citation statements)

References 82 publications

(32 reference statements)

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“…Notably, MeCP2 can recruit the helicase domain of ATRX to heterochromatic foci in living mouse cells in a DNA methylation-dependent manner (Nan et al, 2007). AS is also a genetic disorder characterized by movement disorders, seizures, and mental retardation (Williams et al, 1995;Buoni et al, 1999;Laan et al, 1999). AS model mice show decreased CaMKII activity with concomitant decreases in density and length of dendritic spines in hippocampal and cortical pyramidal neurons (Weeber et al, 2003;Dindot et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Aberrant Calcium/Calmodulin-Dependent Protein Kinase II (CaMKII) Activity Is Associated with Abnormal Dendritic Spine Morphology in theATRXMutant Mouse Brain

Shioda¹,

Beppu²,

Fukuda³

et al. 2011

J. Neurosci.

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In humans, mutations in the gene encoding ATRX, a chromatin remodeling protein of the sucrose-nonfermenting 2 family, cause several mental retardation disorders, including ␣-thalassemia X-linked mental retardation syndrome. We generated ATRX mutant mice lacking exon 2 (ATRX ⌬E2 mice), a mutation that mimics exon 2 mutations seen in human patients and associated with milder forms of retardation. ATRX ⌬E2 mice exhibited abnormal dendritic spine formation in the medial prefrontal cortex (mPFC). Consistent with other mouse models of mental retardation, ATRX ⌬E2 mice exhibited longer and thinner dendritic spines compared with wild-type mice without changes in spine number. Interestingly, aberrant increased calcium/calmodulin-dependent protein kinase II (CaMKII) activity was observed in the mPFC of ATRX ⌬E2 mice. Increased CaMKII autophosphorylation and activity were associated with increased phosphorylation of the Rac1-guanine nucleotide exchange factors (GEFs) T-cell lymphoma invasion and metastasis 1 (Tiam1) and kalirin-7, known substrates of CaMKII. We confirmed increased phosphorylation of p21-activated kinases (PAKs) in mPFC extracts. Furthermore, reduced protein expression and activity of protein phosphatase 1 (PP1) was evident in the mPFC of ATRX ⌬E2 mice. In cultured cortical neurons, PP1 inhibition by okadaic acid increased CaMKII-dependent Tiam1 and kalirin-7 phosphorylation. Together, our data strongly suggest that aberrant CaMKII activation likely mediates abnormal spine formation in the mPFC. Such morphological changes plus elevated Rac1-GEF/PAK signaling seen in ATRX ⌬E2 mice may contribute to mental retardation syndromes seen in human patients.

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Section: Discussionmentioning

confidence: 99%

Aberrant Calcium/Calmodulin-Dependent Protein Kinase II (CaMKII) Activity Is Associated with Abnormal Dendritic Spine Morphology in theATRXMutant Mouse Brain

Shioda¹,

Beppu²,

Fukuda³

et al. 2011

J. Neurosci.

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“…A defect in the gene coding for the E3 ligase E6-AP has been implicated directly as the cause of Angelman syndrome characterized by mental retardation, seizures, out of context frequent smiling and laughter, and abnormal gait (229,251). The target brain protein(s), which are most probably stabilized because of the mutation, has not been identified.…”

Section: Angelman Syndromementioning

confidence: 99%

The Ubiquitin-Proteasome Proteolytic Pathway: Destruction for the Sake of Construction

Glickman

Ciechanover

2002

Physiological Reviews

3,716

3,031

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Between the 1960s and 1980s, most life scientists focused their attention on studies of nucleic acids and the translation of the coded information. Protein degradation was a neglected area, considered to be a nonspecific, dead-end process. Although it was known that proteins do turn over, the large extent and high specificity of the process, whereby distinct proteins have half-lives that range from a few minutes to several days, was not appreciated. The discovery of the lysosome by Christian de Duve did not significantly change this view, because it became clear that this organelle is involved mostly in the degradation of extracellular proteins, and their proteases cannot be substrate specific. The discovery of the complex cascade of the ubiquitin pathway revolutionized the field. It is clear now that degradation of cellular proteins is a highly complex, temporally controlled, and tightly regulated process that plays major roles in a variety of basic pathways during cell life and death as well as in health and disease. With the multitude of substrates targeted and the myriad processes involved, it is not surprising that aberrations in the pathway are implicated in the pathogenesis of many diseases, certain malignancies, and neurodegeneration among them. Degradation of a protein via the ubiquitin/proteasome pathway involves two successive steps: 1) conjugation of multiple ubiquitin moieties to the substrate and 2) degradation of the tagged protein by the downstream 26S proteasome complex. Despite intensive research, the unknown still exceeds what we currently know on intracellular protein degradation, and major key questions have remained unsolved. Among these are the modes of specific and timed recognition for the degradation of the many substrates and the mechanisms that underlie aberrations in the system that lead to pathogenesis of diseases.

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“…Angelman syndrome is a severe neurological disorder characterized by mental retardation, absent speech, ataxia, seizures, and hyperactivity (1). The candidate gene affected is UBE3A, which encodes the E6AP 1 ubiquitin-protein ligase (2,3).…”

mentioning

confidence: 99%

“…The UBE3A locus is imprinted in certain regions of the brain such that only the maternal copy of the gene is expressed (4 -6), and most genetic abnormalities identified in Angelman patients result in the loss of maternal E6AP expression. Approximately 70% of patients possess maternal specific deletions of chromosome 15q11-13, which encompasses the UBE3A locus, 3-4% of patients have two paternal copies of the chromosome, and another 3-4% have defects in which the maternal chromosome possesses the paternal imprint such that no functional maternal copy of UBE3A is present in brain (1).…”

mentioning

confidence: 99%

Biochemical Analysis of Angelman Syndrome-associated Mutations in the E3 Ubiquitin Ligase E6-associated Protein

Cooper

Hudson

Amos

et al. 2004

Journal of Biological Chemistry

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Angelman syndrome is a severe neurological disorder characterized by mental retardation, absent speech, ataxia, seizures, and hyperactivity. The gene affected in this disorder is UBE3A, the gene encoding the E6-associated protein (E6AP) ubiquitin-protein ligase. Most patients have chromosomal deletions that remove the entire maternal allele of UBE3A. However, a small subset of patients have E6AP point mutations that result in single amino acid changes or short in-frame deletions that still allow translation of a full-length protein. By studying these point mutations in E6AP, we found a strong correlation between Angelman-associated mutations and a loss of E3 ubiquitin ligase activity. Interestingly the point mutations affect E6AP activity in different ways. Some mutant proteins cannot form thiol ester intermediates with ubiquitin, others retain the thiol ester formation activity but cannot efficiently transfer ubiquitin to a substrate, and still others are unstable in cells. Our results suggest that the loss of E6AP catalytic activity and likely the improper regulation of E6AP substrate(s) are important in the development of Angelman syndrome.

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Angelman syndrome: a review of clinical and genetic aspects

Cited by 75 publications

References 82 publications

Aberrant Calcium/Calmodulin-Dependent Protein Kinase II (CaMKII) Activity Is Associated with Abnormal Dendritic Spine Morphology in theATRXMutant Mouse Brain

Aberrant Calcium/Calmodulin-Dependent Protein Kinase II (CaMKII) Activity Is Associated with Abnormal Dendritic Spine Morphology in theATRXMutant Mouse Brain

The Ubiquitin-Proteasome Proteolytic Pathway: Destruction for the Sake of Construction

Biochemical Analysis of Angelman Syndrome-associated Mutations in the E3 Ubiquitin Ligase E6-associated Protein

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