Prader-Willi syndrome (PWS) is a rare genetic disorder caused by the loss of genes that normally reside in a particular region of chromosome 15 called the “PWS locus.” These genes control metabolism, appetite, growth, intellectual abilities, and social behavior. Their loss leads to a wide range of symptoms from weak muscle tone to increased appetite, and cognitive and behavioral problems.
Genomic imprinting
Each person has 46 chromosomes arranged in 23 pairs. One copy of each pair comes from the mother and the other from the father. Both paternal and maternal gene copies are often necessary. However, some genes are active only on the copy coming from one parent.
Genomic imprinting is a natural process by which the body silences, or turns off, either the maternal or the paternal copy of a gene. It does so using epigenetic tags or chemical marks on the DNA without affecting the genetic code.
Genomic imprinting normally silences the PWS locus coming from the mother. Therefore, if the paternal copy is missing, the person will have the disease.
How can the genes be missing in PWS?
Three specific defects can lead to PWS. These are DEL15 or the deletion of paternal genes on chromosome 15, maternal uniparental disomy (UPD), and genetic imprinting errors in the region controlling gene activity on chromosome 15.
DEL15
In about 60% of people with the disease, genes on the paternal chromosome 15 are missing, or deleted in the PWS locus.
Because the locus also is inactive on maternal chromosome 15, cells cannot make the proteins that the genes on this locus normally provide instructions to generate.
The deletion of the paternal PWS locus is the result of a random error during the formation of an egg or sperm cell, or during the development of the fetus. So, it is not hereditary. The probability to have a second child with the condition is less than 1%.
UPD
Another mechanism underlying PWS is UPD. Here, a child inherits two copies of chromosome 15 from one parent. In the case of PWS, both copies of chromosome 15 come from the mother where both PWS loci are inactive.
This type of genetic change occurs in about 35% of cases. Similar to DEL15, it results from a random error during the development of the fetus.
Imprinting errors and other genetic alterations
In less than 5% of people with the disease, the PWS locus of the father’s chromosome 15 is present. However, the genes are not functioning. This is because the PSW locus is silenced in the same way as the mother’s.
A small deletion in the paternal imprinting center, a region of the chromosome can cause PWS in this case. Imprinting centers are regions in the genome that control the imprinting process. As such, the PWS locus is inactive in both maternal and paternal copies of chromosome 15, leading to PWS.
In very rare cases, PWS may be the result of translocation in the PWS locus. Here, a portion of a chromosome breaks off and reattaches to a different chromosome. This results in the shifting of genetic material that leads to altered chromosome pairing and affects the normal regulation of genes.
Last updated: March 31, 2021
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