User talk:Z3291643

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1721745/pdf/v089p0F436.pdf--Sang Lee 21:32, 17 August 2011 (EST)

Identify a review and a research article related to your group topic.

This research article showed genotype-phenotype correlations in Angelman Syndrome (AS). They have concluded that deletion patients had worse developmental outcomes than non deletion patients. Abstract at PMID 20729760

This review article is really comprehensive and gives a good background knowledge of AS. Astract at PMID 20445456

--z3291643 21:37, 10 August 2011 (EST)

Timeline

Year	Notes
1965	First reported by Dr Harry Angelman- Initially called this disorder “Happy Puppet Syndrome”
1980s	First reports of AS reaches US and research into the disorder being at the University of Florisa under the direction of Dr. Charles Williams.
1987	Discovery of a genetic marker for AS – an absent genetic code on chromosome 15
1997	The cause of AS discovered by Dr. Joseph Wagstaff and Dr. Arthur Beaudet – mutation or deletion in the UBE3A gene.
Current	Four different genetic abnormalities for AS confirmed by genetic testing; Deletion, Uniparental Disomy (UPD), Imprinting and UBE3A mutation.

--Sang Lee 23:22, 1 September 2011 (EST)

Aetiology

Different genetic mechanisms lead to different clinical phenotypes of AS. The most common genetic mechanism leading to AS is the deletion or re-arrangement of maternal chromosome at locus 15q11.2-q13, accounting 60-75% of AS occurrences. This leads to more severe clinical phenotypes of microcephaly, motor difficulties, seizures and impaired speech development. The next most common genetic mechanism is mutation in the UBE3A gene responsible for 10% of AS cases and paternal uniparental disomy and mutation in the imprinting centre (IC), both accounting 2-5% of AS observed.

AS is caused by the 4 major genetic mechanisms mentioned above and are thus divided into Classes I to IV based on their underlying genetic mechanism. AS patients with the clinical features of AS but no cytogenetic or molecular abnormality in Chromosome 15q11.2-13 are grouped under Class V (summarised in table below).

Class	Mechanism	Diagnostic Tests	Frequency
Ia	De novo deletion	High resolution cytogenetics FISH	60-75%
Ib	Deletion due to chromosome rearrangement	High resolution cytogenetics FISH	<1%
II	Paternal uniparental disomy	RFLP analysis	2%
IIIa	Imprinting defect with IC mutation	Screening of IC for mutations is positive	2%
IIIb	Imprinting defect withouth IC mutation	Screening of IC for mutations is negative	2%
IIIc	Mosaic imprinting defect	Screening of IC for mutations is usually negative	?
IV	UBE3A mutation	Screening of UBE3A for mutations	5-10%
V	No identifiable genetic abnormality	Consider other diagnoses	5-26%
Adapted from Smith JC, et al. Angelman syndrome: a review of the clinical and genetic aspects. J Med Genet 2003;40:87-95

Pathogenesis

Chromosome 15 became associated with AS in the 1980s after the observation of many AS patients harboring microdeletions of 15q11.2-15q13. The last decade has shed even more light in the aetiology of AS,as Kishino and Matsuura first identified UBE3A as the causative gene for AS in 1997. Although the function of UBE3A is known (encodes for a ubiuitin ligase enzyme),its function in the development of the nervous system and the process of UBE3A mutation leading to cognitive impairment in AS patients is still vague. Despite the uncertain progression of UBE3A mutation and the neurological abnormalities characteristic of AS, animal models have illustrated the vital role of UBE3A in the normal functioning of the brain. This can be exemplified by a study which utilized a mouse model with target inactivation of the gene UBE3A resulting in the manifestation of classical features of AS. In addition, the fact that imprinting of UBE3A takes place on ly in specific brain regions (cerebellum, olfactory tracts and the hippocampus) confirms the hypothesis that the loss of this gene would be detrimental in the cognitive development. It is also known that UBE3A plays an important role in synaptic transmission, but exactly how it does so is still not completely understood.

As briefly mentioned above, UBE3A is a member of the E3 ubiquitin ligase family of enzymes, responsible for the addition of ubiquitin to the target protein for degradation of the ubiquitinated protein. These processes are required for normal human cognitive function. In this way synaptic protein Arc(activity-regulated cytoskeleton-associated protein) is degraded to control synaptic function. Arc is a target protein of UBE3A in dendritic spines found in the hippocampal neurons. Deletion UBE3A leads to the accumulation of Arc in neurons leading to trafficking of AMPA receptors, resulting in impaired cognitive functions.

UBE3A ubiqutylation consists of: 1. Activation of ubiquitin by E1 enzyme 2. E1 ezyme transfers ubiquitin to E2 enzyme 3. E2 enzyme transfers ubiquitin to UBE3A 4. UBE3A attaches activated ubiquitin to target protein which is then polyubiquitylated and degraded by 26S proteosome.

Animal models

1. Drosophila

Drosophila is an excellent model to use for better understanding of genetic diseases in humans as they are highly homologous to humnan UBE3A (hUBE3A), illustrating a high evolutionary conservation. Drosophila UBE3A (dUBE3A) encodes a protein with 973 amino oacids where the C-terminal HECT domain of the gene shares 62% commonality with hUBE3A. Studies using the Drosophila model have shown that the functional loss of UBE3A resulted in decreased morphogenesis of terminal dendritic branches. This is of interest as dendritic branches cover over 90% of the neuronal surface where synaptic input between neurons occur. Thus proper formation of dendritic branching is pivitol for proper neuronal function and hence cognitive function. ref><pubmed>18996915</pubmed></ref> Interestingly, overexpression of dUBE3A also gave the same result, consisting of abnormal locomotiona dn decreased dendritic branching in sensory neurons. This suggests a possible research field for some forms of autism where the region containing UBE3A is duplicated, leading to delayed motor skills and seizures.

Phenotype-Genotype correlations

All AS patients show differing extents of cognitive impairment, movement disorder, characteristic behaviours and difficulty in speech and language. However, there seems to be some phenotype-genotype correlations as 5-7Mb deletions result in the most severe phenotypes such as microcephaly, more sever epilepsy and seizures, motor difficulties and language impairment. AS patients with large deletions also present with clinical hypopigmentation, whereas AS patients with uniparental disomy have better physical growth, fewer motor deficits and lower seizure occurrences. The underlying mechanism for AS which gives the least debilitating phenotype is imprinting defects, resulting in higher developmental and language ability than AS caused by other mechanisms.

Complications

Hypopigmentation and Ocular albinism

OCA2 gene, also known as P gene, is closely located to the UBE3A gene. It encodes a protein vital in tyrosine metabolism, which plays a role in pigmentation development of skin, hair and irides. However, AS caused by the large deletion of UBE3A leads to haploinsufficiency of OCA2 gene, resulting in hypopigmentation of the skin and the eyes. In some children with severe hypopigmentation, some form of alibinism is suspected. When AS is caused by another mechanism, no abnormality of the skin and eye pigmentation is observed. However, not all AS children with OCA2 gene deletion will present with obvious hypopigmentation, they may just exhibit lighter skin colour than their parents.

Related Diseases

Prader-Willi Syndrome (PWS)

PWS is a result from the absence of paternally expressed 15q11-q13 gene as a corollary of de novo deletion, maternal uniparental disomy of chromosome 15 or an imprinting defect on paternal chromosome 15 leading to the silencing of paternal alleles. It is characterized by hyperphagia, obesity in later infancy and early childhood and difficulty in feeding during early infancy. There is also cognitive impairment to some extent, though some PWS patients may exhibit intelligence in the normal IQ range. Behavioral phenotypes include stubbornness, manipulative tendency, obsessive compulsive characteristics.

Glossary

Imprint: Genomic imprinting