Prader-Willi syndrome is caused by genetic changes on an "unstable" region of chromosome 15 that affects the regulation of gene expression, or how genes turn on and off. This part of the chromosome is called unstable because it is prone to being shuffled around by the cell's genetic machinery before the chromosome is passed on from parent to child.
The genetic changes that cause Prader-Willi syndrome occur in a portion of the chromosome, referred to as the Prader-Willi critical region (PWCR), around the time of conception or during early fetal development.1 This region was identified in 1990 using genetic DNA probes. Although Prader-Willi syndrome is genetic, it usually is not inherited and generally develops due to deletions or partial deletions on chromosome 15.
Specific changes to the chromosome can include the following:
- Deletions. A section of a chromosome may be lost or deleted, along with the functions that this section supported. A majority of PWS cases result from a deletion in one region of the father's chromosome 15 that leads to a loss of function of several genes.2 The corresponding mother's genes on chromosome 15 are always inactive and thus cannot make up for the deletion on the father's chromosome 15. The missing paternal genes normally play a fundamental role in regulating hunger and fullness.
- Maternal uniparental disomy. A cell usually contains one set of chromosomes from the father and another set from the mother. In ordinary cases, a child has two chromosome 15s, one from each parent. In around one-fourth of PWS cases, the child has two copies of chromosome 15 from the mother and none from the father. Because genes located in the PWCR are normally inactive in the chromosome that comes from the mother, the child's lack of active genes in this region leads to PWS.2
- An imprinting center defect. Genes in the PWCR on the chromosome that came from the mother are normally inactivated, due to a process known as "imprinting" that affects whether the cell is able to "read" a gene or not. In a small percentage of PWS cases, the chromosome 15 inherited from the father is imprinted in the same way as the mother's. This can be caused by a small deletion in a region of the father's chromosome that controls the imprinting process, called the imprinting center.3 In these cases, both of the child's copies of chromosome 15 have inactive PWCRs, leading to Prader-Willi syndrome.2