Cell Biology and Disease:

Angelman Syndrome
By: Kathy Duong, Kaitlyn Greenwood, Aliyah Jackson, Van Hopkins, Allison Weber
 Introduction
● Angelman Syndrome (AS)
○ complex developmental neurological
disorder1
● Dr. Harry Angelman (1965)1,2
● Currently affects 1/12,000-20,000 people2
● Symptoms occur 6-12 months after birth1,2
● Caused by a deletion of chromosome 15q11.2-
q131,2
○ dysfunctional ubiquitination
“Ritratto di fanciullo con disegno” by Giovanni
Francesco Caroto (1480-1555)
Symptoms

Intern, Digital Marketing. “Angelman Syndrome Center.” Achievement

Center of Texas, Achievement Center of Texas, 26 Feb. 2020,
“Tag: Angelman Syndrome.” Patient Talk, 17 Aug. 2018,
achievementcenteroftexas.org/special-needs/angelman-syndrome-
patienttalk.org/tag/angelman-syndrome/.
center/.
Variations in Symptoms
● A large deletion of UBE3A results:
○ skin/eye hypopigmentation
■ closely associated pigment gene can
also be deleted.
○ Hyperthermia
■ multiple medication usage linked to
other medical illnesses.
● AS is commonly misdiagnosed as autism
○ due to similar symptoms
○ shared mutation in the chromosome
15q11.2-q13 region2

Wikipedia contributors. (2020, April 5). Hypopigmentation. In Wikipedia, The Free

Encyclopedia. Retrieved 21:13, April 10, 2020, from
https://en.wikipedia.org/w/index.php?title=Hypopigmentation&oldid=949318828
 Mutations of UBE3A Gene
● On chromosome 154
● 65-75% of cases are full deletions4
● 5-11% are in frame deletions4
● 3-7% are caused by uniparental
disomy4
● About 3% of cases caused by
imprinting defects4

Chamberlain, S. J., and M. Lalande. “Angelman

Syndrome, a Genomic Imprinting Disorder of the
Bai,
Hussain,
Shaochun
Brain.” Bilal.
& Lozada,
Journal “InNeuroscience,
of Frame
Anthony
Deletion.”
& Jones,
vol. Wikipedia,
30, Marilyn
no. 30, 11&Nov.
“Chromosome
Dietz,
2016,
2010,Harry 15.” Wikipedia,
MelissaWikimedia
commons.wikimedia.org/wiki/File:In-
pp. & Dempsey,
9958–9963., & Das, Soma.Foundation,
(2014). 8 Mar.
Mandibuloacral
Frame_deletion_of_a_nucleotide_strand.png.
2020, Dysplasia Caused by LMNA Mutations
en.wikipedia.org/wiki/Chromosome_15.
doi:10.1523/jneurosci.1728-10.2010.
and Uniparental Disomy. Case reports in genetics. 2014.
508231. 10.1155/2014/508231.
Review of Mutated UBE3A Gene

● UBE3A: ubiquitin protein ligase

(E3)
● E3 attaches ubiquitin molecules
on target protein
● Signals degradation
● Other parts:
○ E1: activates ubiquitin w/
ATP
○ E2: transfers ubiquitin to E3
Welchman, Rebecca L., et al. “Ubiquitin and Ubiquitin-
like Proteins as Multifunctional Signals.” Nature Reviews
Molecular Cell Biology, vol. 6, no. 8, Aug. 2005, pp.
599–609., doi:10.1038/nrm1700.
Review of Proteasome Function

● Proteasome degrade proteins

● AKA Ubiquitin Proteasome System
(UPS)
● Proteasome structure:
○ Two 19S or lids
○ 20s or base
○ Make up 26S Proteasome

Lecker, Stewart H, et al. “Protein Degradation by Ubiquitin-Proteasome Pathway in

Normal and Disease States.” American Society of Nephrology, 13 Apr. 2006, pp.
1807–1819., doi: 10.1681/ASN.2006010083.
Cellular Defects
● Aggregated proteins:
○ Misfolded proteins
○ Physical altercations
● Form toxic oligomers
○ Small molecule with repeating
units
○ More damage in greater
quantity
● UBE3A mutation:
○ Unable to mark for
degradation
○ Interfere w/ cellular functions
○ Cell death
Nakamura, Tomohiro, and Stuart A. Lipton. “Cell Death:
6

Protein Misfolding and Neurodegenerative Diseases.” Apoptosis,

vol. 14, no. 4, 9 Jan. 2009, pp. 455–468., doi:10.1007/s10495-
008-0301-y.
 Cellular Defects and Symptoms

● Genomic imprinting leads to only

the maternal allele being active
○ Cerebellum: motor and
emotional control
○ Hippocampus: memory
● Mutations/deletions on the
maternal allele affect brain tissues7

“What Is the Hippocampus? Part I: Episodic Memory and Index Theory.” Camp Hippo, 19 July 2013,
camphippo.wordpress.com/2013/07/14/what-is-the-hippocampus-part-i-episodic-memory-and-index-theory/.
 Cellular Defects and Symptoms
● Proteasome regulation affects synaptic plasticity
○ Alters ability of brain to change/adapt to new
information7, 8
○ Neuronal deficits show in 6-8 weeks in vitro as
UBE3A function is lost9
○ Deficits are:
■ More depolarized resting membrane
potential
■ Immature action potential firing
■ Spontaneous synaptic firing

9
Fink, James J., et al. “Disrupted Neuronal Maturation in
Angelman Syndrome-Derived Induced Pluripotent Stem
Cells.” Nature News, Nature Publishing Group, 24 Apr. 2017,
Top: resting membrane potential
Bottom (left): action potential activity
Bottom (right): spontaneous synaptic activity
 Cellular Defects and Symptoms
● Negatively altered synaptic plasticity results in:
○ developmental delay
○ lack of normal function
○ intellectual disabilities/speech impairment
○ abnormal behaviors
○ memory issues9

● GABA-mediated synaptic transmissions can be negatively

affected
○ Results in epilepsy8

Cherry, Kendra. “Synapses in the Nervous System.”

Verywell Health, Verywell Health, 1 July 2019, “Introduction.” Wiki,
www.verywellhealth.com/synapse-anatomy-2795867. wiki.mcmaster.ca/LIFESCI_4M03/group_2_presentation_2_-_epilepsy.
Summary
● Angelman Syndrome:
○ discovered in 1965
○ Incurable
○ effects ~1/12,000-20,000 people
● Characteristic symptoms of AS include: developmental delay, intellectual
disability, speech impairment, problems with movement and balance (ataxia),
epilepsy, and microcephaly.
● AS is caused by various defects to the maternal 15th chromosome.
● UPS degrades proteins
○ defects of E3: inability to degrade aggregated proteins.
● Deletion of UBE3A negatively affects neural tissue, including proteasome
regulation and synaptic plasticity, resulting in AS symptoms.
 Citations
1. “Angelman Syndrome - Genetics Home Reference - NIH.” U.S. National Library of Medicine, National Institutes of Health, 2020,
ghr.nlm.nih.gov/condition/angelman-syndrome.
2. Margolis, Seth S, et al. “Angelman Syndrome.” Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics, Springer US, July
2015, www.ncbi.nlm.nih.gov/pubmed/26040994.
3. Vachiramon V. A concise approach to childhood hypopigmentation. J Cutan Aesthet Surg. 2013;6(2):73–74.
4. Tomaić, V, and L Banks. “Angelman Syndrome-Associated Ubiquitin Ligase UBE3A/E6AP Mutants Interfere with the Proteolytic Activity of the Proteasome.” Cell
Death & Disease, vol. 6, no. 1, 2015, doi:10.1038/cddis.2014.572.
5. Atkin, Graham, and Henry Paulson. “Ubiquitin Pathways in Neurodegenerative Disease.” Frontiers in Molecular Neuroscience, vol. 7, 8 July 2014,
doi:10.3389/fnmol.2014.00063.
6. Nakamura, Tomohiro, and Stuart A. Lipton. “Cell Death: Protein Misfolding and Neurodegenerative Diseases.” Apoptosis, vol. 14, no. 4, 9 Jan. 2009, pp. 455–468.,
doi:10.1007/s10495-008-0301-y.
7. UBE3A gene - Genetics Home Reference - NIH. (n.d.). Retrieved from https://ghr.nlm.nih.gov/gene/UBE3A#resources.
8. Pelc, K., Boyd, S. G., Cheron, G., & Dan, B. (2007, September 29). Epilepsy in Angelman syndrome. Retrieved from
https://www.sciencedirect.com/science/article/pii/S1059131107001872.
9. Fink, James J., et al. “Disrupted Neuronal Maturation in Angelman Syndrome-Derived Induced Pluripotent Stem Cells.” Nature News, Nature Publishing Group, 24
Apr. 2017, www.nature.com/articles/ncomms15038.
10. Sun, J., Zhu, G., Liu, Y., Standley, S., Ji, A., Tunuguntla, R., Wang, Y., Claus, C., Luo, Y., Baudry, M., & Bi, X. (2015). UBE3A Regulates Synaptic Plasticity and
Learning and Memory by Controlling SK2 Channel Endocytosis. Cell reports, 12(3), 449–461. https://doi.org/10.1016/j.celrep.2015.06.023.