A new visualization tool, created by Dutch researchers, details the genetic pathways of deleted genes in Prader-Willi syndrome (PWS) and Angelman syndrome (AS), showing that some common symptoms are caused by multiple genes.
Humans have two sets of chromosomes — one from the mother and one from the father. Prader-Willi and Angelman syndromes are both caused by a deletion of a part of chromosome 15 known as 15q11.2-q13. However, Prader-Willi occurs if the deletion is on chromosome 15 of paternal origin, while Angelman occurs if it is on the maternal origin one.
Even though both syndromes are the result of a deletion in the same region, it is the deletion of different genes that is responsible for the two distinct sets of symptoms in these patients.
Using data collected from literature research, genome browsers, and pathway databases, researchers sought to identify the distinct molecular interactions in these patients and determine how deletion of the genes in both syndromes is involved in disease development.
As a result, the team created a pathway visualization tool covering all the molecular pathways found, showing for the first time that several symptoms may have their molecular origin in more than one gene.
While both Prader-Willi and Angelman patients exhibit hypotonia (low muscle tone) as babies, delays in development, and loss of skin color (hypopigmentation), Angelman patients also have severe developmental delays, tend to be unnaturally happy, and can have epileptic seizures.
Prader-Willi patients, on the other hand, have hyperphagia (abnormally increased appetite for food), which leads to obesity, the major cause of mortality, and hypogonadism (reduction or absence of hormone secretion).
Researchers found that loss of the GABRB3 gene can lead to epilepsy, cleft palate, and hypersensitive behavior in Angelman patients. Moreover, loss of this gene, which in turn causes impairment in the expression of another gene — OCA2 — may be behind the hypopigmentation observed in both Prader-Willi and Angelman syndrome.
Three genes — MAGEL2, SNORD116 and SNORD115 — are thought to contribute to the abnormally increased appetite observed in Prader-Willi, while two genes — MAGEL2 and NDN — are behind the incorrect development of the brain in these patients, and possibly the hypothalamus, the region responsible for hormone control.
This collection and visualization of all available knowledge of molecular interactions and downstream pathways of genes in both Prader-Willi and Angelman syndromes “reveals gaps of knowledge which should be closed in future research,” the authors said.
Researchers uploaded their pathway visualization tool to the online open pathway database WikiPathways, which is a user-curated database that allows the collection, visualization, and publishing of new biological pathways by both medical professionals and bioinformaticians. On this online database, a newly created pathway can be shared and accessed by other researchers quickly and easily.