Genes in the BP1/BP2 interval on chromosome 15 identified

New research has identified genes affected in Prader-Willi patients by deletion. Deletions account for approximately 70% of PWS cases. There are two different sizes of deletion, with one type encompassing more genes than the other.

The new article is from Dr. Rob Nicholl's group. Here is the link to the abstract if you want to take a look. Identification of Four Highly Conserved Genes between Breakpoint Hotspots BP1 and BP2 of the Prader-Willi/Angelman Syndromes Deletion Region That Have Undergone Evolutionary Transposition Mediated by Flanking Duplicons

This may fall into the category of "more than I really want to know"-- not in a bad way --- it's just a lot of nitty-gritty genetics. Here is a quick synopsis:

When PWS is caused by a deletion, there are actually two different classes of deletions (type I and type II). Both occur at a fixed position on one end of the chromosome, but there are two different spots where the break can occur at the other end. Depending on which spot the break occurs at that end, you will have up a smaller or bigger deletion. Both types of deletion are detected by FISH or methylation testing, and you can't tell the which type of deletion your child has by those tests -everybody looks the same. This study defines those genes that are between the two potential breakpoints (ie, those gene lost in the bigger deletion, but retained in the smaller deletion).

Four genes are identified to fall between the breakpoints - two are new genes with as yet unknown functions, and two have been previously described. Of those that have been previously described - the CYFIP1 gene-- encodes a protein that has been implicated as being involved with other proteins in a different form of mental retardation (Fragile X syndrome), and CYFIP1 looks to be important in maintaining the structure of neurons in the brain. The other previously described protein is important in cell structure. The paper also discusses the structure of chromosome 15 in the PWS region, and how repetitive DNA sequences in the area predispose the PWS region to the deletions that ultimately cause PWS.

What does this mean for you??
It's not clear if it has any significance for the UPD PWS patient. Those individuals will have both copies all 4 of these particular genes and the genes are not imprinted, so they probably function as normal.
For PWS deletion patients with a smaller deletion, these genes are present and probably fuctioning normally (this is not tested in this paper). For PWS deletion patients with a larger deletion, these genes are missing on the deleted chromosome, present and presumably functioning on the other, so you would expect they might express half the normal level of these 4 genes, and this may contribute to a more severe phenotype. This may well explain some of the variability of PWS severity, although a significant amount of work (with large numbers of well characterized PWS del subjects) will have to be done to really demonstrate this. Again note that type I vs. type II deletions are not routinely determined in the clinic.

I hope this is not too confusing -- but once again I am reminded of the genetic complexity of this syndrome.

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Theresa Strong


Theresa V. Strong, Ph.D., received a B.S. from Rutgers University and a Ph.D. in Medical Genetics from the University of Alabama at Birmingham (UAB). After postdoctoral studies with Dr. Francis Collins at the University of Michigan, she joined the UAB faculty, leading a research lab focused on gene therapy for cancer and directing UAB’s Vector Production Facility. Theresa is one of the founding members of FPWR and has directed FPWR’s grant program since its inception. In 2016, she transitioned to a full-time position as Director of Research Programs at FPWR. She remains an Adjunct Professor in the Department of Genetics at UAB. She and her husband Jim have four children, including a son with PWS.

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