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What is Prader-Willi Syndrome?
Prader-Willi Syndrome (PWS) is a complex, multisystem genetic disorder generally resulting from a deletion on the paternal chromosome 15. The disease is caused by a hypothalamus defect leading to problems with control of hunger, thirst, and release of hormones responsible for growth and sexual development (4). The deletion region includes many imprinted genes, including the gene of focus for this website- NDN/necdin.
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What is NDN/Necdin and how is it involved?
Necdin stands for "neurally differentiated embryonal carcinoma-cell derived factor" and is an intronless gene that is located in the Prader-Willi syndrome deletion region between 15q11-q13 (1,5, 6). It is imprinted and expressed only from the paternal allele (6). It is found to be a growth suppressor facilitating the entry of the cell into cell cycle arrest, interacting with p53 in order to inhibit cell growth (7).
Necdin is a part of the MAGE superfamily of proteins. The MAGE proteins are split into two types, Type I having expression in tumor cells and Type II having expression in differentiated cells, of which necdin is a part (10). Indeed, necdin protein is localized to the nuclei of post-mitotic neurons within the central nervous system from beginning of neural differentiation on (8). It is also present in all other tissues of the body, with highest amounts in the brain and placenta (8). NDN has been shown to play a role in cell growth suppression via cell cycle arrest in terminally differentiated neurons by facilitating entry of the cell into the cell cycle and acting as a transcriptional repressor (5, 9, 10). It has also been found to have a role in stem cell differentiation of other types of tissues, including adipose, blood vessels and cells, and muscle, among others (9). The combination of these many roles play into many symptoms of Prader-Willi Syndrome.
Research shows that NDN is only transcribed from one of the two parental alleles, and is thus imprinted meaning that NDN expression can only occur due to transcription from the paternal chromosome and not from the maternal chromosome. (8). Below there is further discussion of imprinting.
In PWS, NDN and the other PWS genes are deleted in some way on the paternal allele. This loss of NDN possibly contributes to a range of symptoms of PWS, due to its function in neural differentiation. While the PWS symptoms caused by NDN loss specifically have not all been isolated, it is probable that NDN loss plays a great role in the mental retardation and other neural defects of PWS individuals.
Necdin is a part of the MAGE superfamily of proteins. The MAGE proteins are split into two types, Type I having expression in tumor cells and Type II having expression in differentiated cells, of which necdin is a part (10). Indeed, necdin protein is localized to the nuclei of post-mitotic neurons within the central nervous system from beginning of neural differentiation on (8). It is also present in all other tissues of the body, with highest amounts in the brain and placenta (8). NDN has been shown to play a role in cell growth suppression via cell cycle arrest in terminally differentiated neurons by facilitating entry of the cell into the cell cycle and acting as a transcriptional repressor (5, 9, 10). It has also been found to have a role in stem cell differentiation of other types of tissues, including adipose, blood vessels and cells, and muscle, among others (9). The combination of these many roles play into many symptoms of Prader-Willi Syndrome.
Research shows that NDN is only transcribed from one of the two parental alleles, and is thus imprinted meaning that NDN expression can only occur due to transcription from the paternal chromosome and not from the maternal chromosome. (8). Below there is further discussion of imprinting.
In PWS, NDN and the other PWS genes are deleted in some way on the paternal allele. This loss of NDN possibly contributes to a range of symptoms of PWS, due to its function in neural differentiation. While the PWS symptoms caused by NDN loss specifically have not all been isolated, it is probable that NDN loss plays a great role in the mental retardation and other neural defects of PWS individuals.
What is Imprinting? (11)
Imprinting is a form of epigenetics, or changes to the structure of the DNA that are not caused by the genes themselves. In imprinting, a gene or group of genes is methylated on a certain chromosome so that expression of those genes is repressed as seen in this figure:
This methylation is passed through generations from either the mother's eggs or father's sperm and is not cleared as other methylations of the genome are during development.
In the case of NDN and other genes in the Prader-Willi Syndrome region, the maternal chromosome region is methylated so that expression of these genes can only come from the paternal chromosome. Disorders connected with imprinting occur, when the unmethylated chromosome has a deletion or other defect so that expression cannot occur from that chromosome either.
This methylation is passed through generations from either the mother's eggs or father's sperm and is not cleared as other methylations of the genome are during development.
In the case of NDN and other genes in the Prader-Willi Syndrome region, the maternal chromosome region is methylated so that expression of these genes can only come from the paternal chromosome. Disorders connected with imprinting occur, when the unmethylated chromosome has a deletion or other defect so that expression cannot occur from that chromosome either.
Three Genetic Mechanisms of Prader-Willi Syndrome (1)
1) Deletion (about 70% of cases): This occurs when a paternally inherited chromosome 15 is missing a portion of its genes, particularly the 15q11- q13 portion, or the PWS genes. Typically deletions occur spontaneously and are unlikely to occur in a subsequent pregnancy.
2)Maternal Uniparental Disomy (about 25% of cases): This occurs when a child inherits both of his/her mother's chromosome 15's. The condition usually originates as trisomy 15 and results in loss of the paternal chromosome. Because the PWS genes are imprinted on the maternal chromosome, the genes are not expressed as if they were deleted. 3) Methylation Defect (Less than 5% of cases): This occurs when the PWS genes are present but are not expressed do to an imprinting defect, usually due to a deletion in the imprinting center within chromosome 15. This deletion leads to situations in which the paternal genes are imprinted just as the maternal genes are. |
Works Cited:
1) http://www.pwsausa.org/about-pws/basic-facts-about-pws
2) Cassidy, Suzanne B. http://jmg.bmj.com/content/34/11/917.full.pdf+html
3) http://ghr.nlm.nih.gov/condition/prader-willi-syndrome
4) http://www.mayoclinic.org/diseases-conditions/prader-willi-syndrome/basics/treatment/con-20028982
5) Ren, et al. http://www.jneurosci.org/content/23/5/1569.long
6) http://www.ncbi.nlm.nih.gov/gene/4692
7) NDN - Necdin - Homo sapiens (Human). (n.d.). Retrieved February 26, 2015, from http://www.uniprot.org/uniprot/Q99608
8) Macdonald, H., & Wevrick, R. (1997). The Necdin Gene is Deleted in Prader-Willi Syndrome and is Imprinted in Human and Mouse. Human Molecular Genetics,6(11), 1873-1878.
9) Asai et al. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3757235/
10) Taniura et al.
11) http://missinglink.ucsf.edu/lm/genes_and_genomes/imprinting.html
1) http://www.pwsausa.org/about-pws/basic-facts-about-pws
2) Cassidy, Suzanne B. http://jmg.bmj.com/content/34/11/917.full.pdf+html
3) http://ghr.nlm.nih.gov/condition/prader-willi-syndrome
4) http://www.mayoclinic.org/diseases-conditions/prader-willi-syndrome/basics/treatment/con-20028982
5) Ren, et al. http://www.jneurosci.org/content/23/5/1569.long
6) http://www.ncbi.nlm.nih.gov/gene/4692
7) NDN - Necdin - Homo sapiens (Human). (n.d.). Retrieved February 26, 2015, from http://www.uniprot.org/uniprot/Q99608
8) Macdonald, H., & Wevrick, R. (1997). The Necdin Gene is Deleted in Prader-Willi Syndrome and is Imprinted in Human and Mouse. Human Molecular Genetics,6(11), 1873-1878.
9) Asai et al. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3757235/
10) Taniura et al.
11) http://missinglink.ucsf.edu/lm/genes_and_genomes/imprinting.html
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