This web page was produced as an assignment for Genetics 564, an undergraduate capstone course at UW-Madison.
What is Angelman Syndrome?
Angelman Syndome (AS) is a rare genetic disorder that affects the nervous system. Neurological outcomes of AS include intellectual disability as well as impairments of balance and speech [1]. Some cases also involve epilepsy and microcephaly. Individuals with AS begin showing symptoms between 6 months to a year of age due to delayed development [1]. Classic symptoms vary between children and adults. Children with AS are often happy and excitable, with characteristic outbursts of laughter and hand-flapping. In adults, excitability and sleeping issues often seen in childhood tend to subside.
What causes Angelman Syndrome?
In most patients, AS is caused by an inactive form of a gene on the maternal chromosome 15 [2]. However, cases involve symptoms that are caused by unknown genetic factors. Investigating the alternate mechanisms that contribute to AS may shed light on the source of these alternate symptoms, such as epilepsy, a neuronal disorder. There are many genes involved in neuronal function that may be possible contributors to epilepsy in AS patients, one of them being the SNRPN gene [3].
What is SNRPN?
Small nuclear ribonucleoprotein polypeptide N (SNRPN) is a protein involved in pre-mRNA processing, such as splicing. SNRPN is expressed at high levels in the brain, contributing to RNA processing in neurons [3]. In 10% of AS cases, patients have a deletion in the SNRPN gene, but it is unknown how this may contribute pathology [4]. Since only certain patients with AS possess a deletion in the SNRPN gene, it may explain why different symptoms are experienced among patients, such as epilepsy.
What is splicing?
DNA is the genetic code; it’s what makes us, us. In order to be expressed, DNA must be transcribed first into RNA. However, this RNA must be processed into mRNA to be fully mature. To accomplish this, splicing must occur. Splicing consists of removing introns (RNA segments that do not code for proteins) so that only exons (RNA segments that code for proteins) remain. This mature mRNA transcript now can eventually be translated into proteins. SNRPN is one of the proteins that help accomplish the process of splicing.
Figure 1. The splicing process. In this process, SNRPN and other proteins associate with RNAs, called snRNAs, in the cell nucleus to form snRNPs. snRNPs coordinate to form a complex called the spliceosome, which is responsible for processing pre-mRNA into mature RNA so that it can leave the nucleus and be translated into proteins [5].
What role does SNRPN play in disease?
It is known that SNRPN is expressed at high levels in neurons and is involved in RNA processing [6]. Dysfunctional RNA processing in neurons can lead to neurodegeneration, which can cause epilepsy [7][8]. Only about 10% of AS cases involve an SNRPN deletion, but this may explain why only certain patients with AS experience epilepsy. This deletion may lead to an inactive or aberrant form of SNRPN, affecting proper splicing in neurons. Neuronal dysfunction is often attributed to defects in RNA processing[9]. In addition, RNA processing defects can lead to neurodegeneration associated with epilepsy[10]. It is known that patients with specific SNRPN mutations have epileptic phenotypes, yet the molecular mechanism by which this occurs is unknown[11].
References
[1] Angelman Syndrome: Genetics Home Reference <https://ghr.nlm.nih.gov/condition/angelman-syndrome>
[2] Chamberlain, S. J., & Lalande, M. (2010). Angelman Syndrome, a Genomic Imprinting Disorder of the Brain. Journal of Neuroscience, 30(30), 9958-9963. doi:10.1523/jneurosci.1728-10.2010 <http://www.jneurosci.org/content/30/30/9958>
[3] Varon, R., Horn, D., Cohen, M. Y., Wagstaff, J., Horsthemke, B., Buiting, K., … Gillessen-Kaesbach, G. (2004). SNURF-SNRPN and UBE3A transcript levels in patients with Angelman syndrome. Human Genetics, 114(6), 553-561. doi:10.1007/s00439-004-1104-z <https://www.ncbi.nlm.nih.gov/pubmed/15014980>
[4] Farber, C. (1999). The chromosome 15 imprinting centre (IC) region has undergone multiple duplication events and contains an upstream exon of SNRPN that is deleted in all Angelman syndrome patients with an IC microdeletion. Human Molecular Genetics, 8(2), 337-343. doi:10.1093/hmg/8.2.337 <https://academic.oup.com/hmg/article/8/2/337/585544/The-Chromosome-15-Imprinting-Centre-IC-Region-Has>
[5] Blogos <http://hermeticlessons.blogspot.com/2015_03_01_archive.html>
[6] Li, H., Zhao, P., Xu, Q., Shan, S., Hu, C., Qiu, Z., & Xu, X. (2016). The autism-related gene SNRPN regulates cortical and spine development via controlling nuclear receptor Nr4a1. Scientific Reports, 6, 29878. doi:10.1038/srep29878
<https://www.ncbi.nlm.nih.gov/pubmed/1533223>
[7] Neuropathology: An illustrated interactive course for medical students and residents <http://neuropathology-web.org/chapter9/chapter9hAtaxia.html>
[8] European Commission: Neurodegenerative Disorders <http://ec.europa.eu/health/major_chronic_diseases/diseases/brain_neurological_en>
[9] Gallo, J. . (2005). The role of RNA and RNA processing in Neurodegeneration. Journal of Neuroscience, 25(45), 10372–10375. doi:10.1523/jneurosci.3453-05.2005
< http://www.jneurosci.org/content/25/45/10372 >
[10] Battaglia, A., Gurrieri, F., Bertini, E., Bellacosa, A., Pomponi, M. G., Paravatou-Petsotas, M., . . . Neri, G. (1997). The inv dup(15) syndrome: A clinically recognizable syndrome with altered behavior, mental retardation, and epilepsy. Neurology, 48(4), 1081-1086. doi:10.1212/wnl.48.4.1081
<https://www.ncbi.nlm.nih.gov/pubmed/9109904>
[11] Johnstone, K. A. (2005). A human imprinting centre demonstrates conserved acquisition but diverged maintenance of imprinting in a mouse model for Angelman syndrome imprinting defects. Human Molecular Genetics, 15(3), 393-404. doi:10.1093/hmg/ddi456
<https://www.ncbi.nlm.nih.gov/pubmed/16368707?dopt=Abstract>
[2] Chamberlain, S. J., & Lalande, M. (2010). Angelman Syndrome, a Genomic Imprinting Disorder of the Brain. Journal of Neuroscience, 30(30), 9958-9963. doi:10.1523/jneurosci.1728-10.2010 <http://www.jneurosci.org/content/30/30/9958>
[3] Varon, R., Horn, D., Cohen, M. Y., Wagstaff, J., Horsthemke, B., Buiting, K., … Gillessen-Kaesbach, G. (2004). SNURF-SNRPN and UBE3A transcript levels in patients with Angelman syndrome. Human Genetics, 114(6), 553-561. doi:10.1007/s00439-004-1104-z <https://www.ncbi.nlm.nih.gov/pubmed/15014980>
[4] Farber, C. (1999). The chromosome 15 imprinting centre (IC) region has undergone multiple duplication events and contains an upstream exon of SNRPN that is deleted in all Angelman syndrome patients with an IC microdeletion. Human Molecular Genetics, 8(2), 337-343. doi:10.1093/hmg/8.2.337 <https://academic.oup.com/hmg/article/8/2/337/585544/The-Chromosome-15-Imprinting-Centre-IC-Region-Has>
[5] Blogos <http://hermeticlessons.blogspot.com/2015_03_01_archive.html>
[6] Li, H., Zhao, P., Xu, Q., Shan, S., Hu, C., Qiu, Z., & Xu, X. (2016). The autism-related gene SNRPN regulates cortical and spine development via controlling nuclear receptor Nr4a1. Scientific Reports, 6, 29878. doi:10.1038/srep29878
<https://www.ncbi.nlm.nih.gov/pubmed/1533223>
[7] Neuropathology: An illustrated interactive course for medical students and residents <http://neuropathology-web.org/chapter9/chapter9hAtaxia.html>
[8] European Commission: Neurodegenerative Disorders <http://ec.europa.eu/health/major_chronic_diseases/diseases/brain_neurological_en>
[9] Gallo, J. . (2005). The role of RNA and RNA processing in Neurodegeneration. Journal of Neuroscience, 25(45), 10372–10375. doi:10.1523/jneurosci.3453-05.2005
< http://www.jneurosci.org/content/25/45/10372 >
[10] Battaglia, A., Gurrieri, F., Bertini, E., Bellacosa, A., Pomponi, M. G., Paravatou-Petsotas, M., . . . Neri, G. (1997). The inv dup(15) syndrome: A clinically recognizable syndrome with altered behavior, mental retardation, and epilepsy. Neurology, 48(4), 1081-1086. doi:10.1212/wnl.48.4.1081
<https://www.ncbi.nlm.nih.gov/pubmed/9109904>
[11] Johnstone, K. A. (2005). A human imprinting centre demonstrates conserved acquisition but diverged maintenance of imprinting in a mouse model for Angelman syndrome imprinting defects. Human Molecular Genetics, 15(3), 393-404. doi:10.1093/hmg/ddi456
<https://www.ncbi.nlm.nih.gov/pubmed/16368707?dopt=Abstract>
Contact
This website was created by Julie A. Fischer
email: [email protected]
page last updated: 03.09.2017
www.genetics564.weebly.com
email: [email protected]
page last updated: 03.09.2017
www.genetics564.weebly.com