The Genetics of PWS: An Explaination for the Rest of Us

By Linda Keder, Editor, The Gathered View
(Reproduced with permission from The Gathered View)

When the medical world first learned about Prader-Willi syndrome in 1956, doctors had no idea what caused people to have this collection of features and problems that we now know as PWS. It is only in the past 20 years that researchers have discovered the genetic changes on chromosome 15 that are responsible for the syndrome. In 1981, Dr. David Ledbetter and his colleagues reported a breakthrough discovery: They found that many people with PWS had the same segment of genes missing from one of their chromosomes. They had discovered the deletion on chromosome 15 that accounts for more than half of the cases of PWS. Since then, researchers have made a series of other important discoveries about the genes involved in Prader-Willi Syndrome. Thanks to their perseverance, we now know that there are several genetic forms of this complex disorder, and we have genetic tests that can confirm nearly every case.

Chromosomes and Genes: The Basics

To understand the genetics of PWS, you first need a basic understanding of chromosomes and genes. Chromosomes are tiny structures that are present in nearly every cell of our bodies. They are the packages of genes we inherit from our parents. Genes contain all the detailed instructions our bodies need to grow, develop, and function properly-our DNA. Specific genes direct our cells to produce proteins, enzymes, and other essential substances. Each of our approximately 100,000 genes is located on a specific chromosome. Identifying the exact locations and order of genes is a goal of the Human Genome Project, an international research effort. Most of our body's cells contain 46 chromosomes - 23 inherited from our mother and 23 from our father. (Egg and sperm cells normally contain just 23 chromosomes, because those are the cells that join in conception and provide the baby the right number of chromosomes.)

Twenty-two of the chromosome pairs are labeled with a number based on their size (chromosome 1 is the largest pair, and chromosome 22 is the smallest), and the two chromosomes in each numbered pair contain the same genes (one set from mother and one from father). The changes that cause Prader-Willi syndrome occur on the pair known as chromosome 15. The 23rd chromosome pair has a letter name, and it is the pair that determines the baby's sex: Xx for a girl, XY for a boy. Changes or errors in genes and chromosomes are common in the formation of egg and sperm cells. Some of these genetic changes will have no effect when a baby is conceived; some will cause a miscarriage; and some, like those in Prader-Willi syndrome, will cause significant differences in how the baby develops and functions. While many genetic disorders are hereditary (passed down from parent to child) and are caused by a change in a single gene, PWS is more complicated.

Researchers have learned that:

  • More than one gene is involved in PWS, and these genes are near each other in a small area of what is called the "long arm", of chromosome l5-in a region labeled 15q11-q13. Scientists still don't know exactly how many genes and which specific ones are involved.
  • There are at least three different chromosome errors that can keep these key genes from working, and this is what causes the characteristics of PWS.
  • The two most common errors that cause PWS can occur in any conception-in other words, PWS is not usually an inherited condition; it just happens.

The Mystery of Genetic Imprinting

During the 1980s, scientists puzzled over why some people who seemed to have PWS did not have a chromosome deletion, and why some people with the chromosome 15 deletion seemed to have a different condition from PWS. The next breakthough came in 1989, when Dr. Robert Nicholls and fellow researchers announced their discovery that PWS is an example of "genetic imprinting," a process well known in plant genetics but not previously identified in humans. What this means is that some of our genes have to come from a particular parent in order to work (normally, genes work no matter which parent they come from). These rare genes are said to be "imprinted" - they are either turned "on" or "off" depending on which parent contributed the gene. In what scientists call the "Prader-Willi region" of chromosome 15 (the area where the deletion occurs), there are two or more genes that must come from the baby's father in order to work, In Prader-Willi syndrome, these critical genes are either missing, or they were not properly imprinted to be turned "on" in the chromosome that came from the father. (See Genetic Forms of PWS)

Also in the chromosome 15q11 -q13 region is one gene that is imprinted to be turned "on" only in the mother's chromosome. When this gene is missing or not working properly on the mother's chromosome 15, the result is an entirely different syndrome called Angelman syndrome (AS). This discovery explained the mysterious cases of people who had a chromosome 15 deletion but did not have the characteristics of PWS- their deletion was on the chromosome 15 that came from the mother. Because the genetic errors happen in the same section of chromosome 15, PWS and AS are sometimes called "sister" syndromes even though the disorders are not alike.