Scientists have found a gene that causes Weaver syndrome, a rare genetic disorder that typically causes large size at birth, tall stature, developmental delay during childhood, and intellectual disability. Published recently in the American Journal of Human Genetics, the discovery means that testing the EZH2 gene for mutations could help families who are seeking a diagnosis for their child.

“For the families among whom we identified the gene, this discovery definitively brings the diagnostic odyssey to a close — it’s DNA confirmation that their children have Weaver syndrome,” says Dr. William Gibson, the study’s lead investigator. Dr. Gibson is a clinician scientist at the Child & Family Research Institute at BC Children’s Hospital and an assistant professor in the Department of Medical Genetics at the University of British Columbia (UBC).

“Our discovery enables DNA-based diagnostic testing for this particular disease,” says Dr. Gibson. “For physicians who suspect Weaver syndrome in one of their patients, we can now confirm it if we find mutations in EZH2. There may still be other Weaver syndrome genes, and we need to study more families to be sure.”

Presently, doctors diagnose Weaver syndrome by assessing a child’s face, growth, skeleton and other clinical features. People with Weaver syndrome have an oversized head, typical facial features, problems with muscle tone and joints, and differences in the way their skeleton matures. Mutations in the NSD1 gene, which normally causes a rare disease called Sotos syndrome, are also known to cause Weaver syndrome in some cases. There may be other genes involved in Weaver syndrome that are yet to be discovered.

“Now we have an answer for these families and we are also in a position to provide answers to other families affected by this rare and difficult disease,” says Dr. Gibson. He is available to see new patients clinically for diagnosis of Weaver syndrome. As a result of this discovery, Dr. Gibson’s team now offers sequencing of the EZH2 gene on a research basis in partnership with the Ottawa Hospital Research Institute.

Traditionally, hunting for a disease-causing gene has relied on tracking a gene throughout a family’s history. However, Weaver syndrome usually occurs only once in a family, as it is thought to be caused by a new genetic mutation in the sperm or egg that conceived the child. For this study, the investigators sought patients with Weaver syndrome from Canada and the United States. They approached Dr. David Weaver, who discovered the syndrome in 1974 and is professor emeritus of Medical and Molecular Genetics at Indiana University School of Medicine in Indianapolis. In two families that Dr. Weaver had examined, the Canadian team looked for brand new genetic mutations by comparing the DNA of affected children to DNA from their unaffected parents. Once the investigators identified EZH2 as a candidate gene, they sequenced it in DNA samples from a third Canadian family. They confirmed that an EZH2 mutation was in this third family’s child but not in either of her healthy parents.

EZH2 is a cancer gene that is known to be mutated in leukemia, B-cell lymphomas and some other blood cancers. The gene helps control how DNA is packaged around specific proteins, which in turn helps to regulate which groups of genes are turned off and on.

“Our finding illuminates an emerging area of biology that links developmental syndromes and cancer,” says Dr. Gibson. “It appears that some mutations in EZH2, if these occur early in life, produce developmental syndromes such as Weaver syndrome, whereas mutations in the same gene that occur later in life can produce cancer.”

written by Journal of Proteomics and Bioinformatics

If you wanted to draw your family tree, you could start by searching for people who share your surname. Cells, of course, don’t have surnames, but scientists at the European Molecular Biology Laboratory (EMBL) in Heidelberg, Germany, have found that genetic switches called enhancers, and the molecules that activate those switches — transcription factors — can be used in a similar way, as clues to a cell’s developmental history.

The study, published February 3 in Cell, also unveils a new model for how enhancers function.

Looking at fruit fly embryos, Guillaume Junion and Mikhail Spivakov, collaborating scientists in the groups of Eileen Furlong at EMBL and Ewan Birney at EMBL’s European Bioinformatics Institute (EMBL-EBI), found that, in heart muscle cells, enhancers which are meant to be active aren’t the only ones that have groups of transcription factors attached. Surprisingly, enhancers that should be active only in the neighbouring gut muscle were also occupied by transcription factors in heart cells.

“Although it may seem counter-intuitive to leave unnecessary genetic switches available for activation and then have to actively suppress them, the findings make sense in developmental terms,” says Furlong.

Both heart and gut muscle cells develop from the same pool of precursor cells. Enhancers for both groups seem to be made available to transcription factors in the precursor cells, before they ‘grow up’ to be either heart or muscle cells. If this is the case, scientists could work out the relationships between cells by looking at what occupied enhancers they share.

Intriguingly, heart muscle cells don’t actually have the transcription factors that bind to gut enhancers in gut muscle cells. Instead, the gut enhancers in heart cells were occupied by transcription factors produced only by the heart.

Furlong and colleagues found that transcription factors are able to attach themselves to enhancers in groups, with some transcription factors binding directly to the enhancer’s DNA and others binding to those enhancer-bound transcription factors. This means that the genetic sequence of these enhancers can vary greatly, yet they are occupied as a united group — a strategy that differs from the two ways in which enhancers were already known to function. This flexibility in the enhancer’s genetic sequence means that it can mutate without disastrous effects, giving it some evolutionary flexibility.

The EMBL scientists are now investigating how far that flexibility extends. They are looking at variation between species, extending their studies to another species of fruit fly, Drosophila virilis, which is, genetically speaking, as different from the commonly-used Drosophila melanogaster as humans are from chickens.

Fruit fly embryo showing the cells that will become gut (green/yellow) and heart (red) muscle.

written by Journal of Proteomics and Bioinformatics

In the first comprehensive census of human cells’ export workers, scientists at EMBL Heidelberg, found an unexpected variety of genes involved in transporting molecules to the cell membrane and beyond.

Scientists at the European Molecular Biology Laboratory (EMBL) in Heidelberg, Germany, have conducted the first comprehensive census of human cells’ export workers.

Using a combination of genetics and sophisticated microscopy, Rainer Pepperkok and colleagues systematically silenced each of our 22 000 genes, and observed to what extent this affected the cell’s ability to transport a protein. They found that 15% of human genes somehow influence this transport network — known as the secretory pathway — including genes that provide a link to other events in and around the cell. Their findings suggest, for instance, that our cells evolved a complex strategy for adapting to changes in their environment. When a cell senses a growth factor called EGF in its surroundings, a protein on the cell membrane aptly named the EGF receptor is taken from the membrane into the cell, starting a chain reaction that ultimately leads the cell to divide, and during which the EGF receptor is degraded. The EMBL scientists have now found that the process also triggers an increase in activity at the early steps of the secretory pathway to transport newly synthesised EGF receptor back to the membrane, where it will be needed again.

Next, the scientists would like to tease out how mechanisms like sensing the environment, controlling genes and transmitting signals are connected to transporting molecules to the membrane, in an effort to better understand how cells work as whole.

The study’s data is freely available to the scientific community at www.mitocheck.org, alongside results of previous screens focused on essential cellular functions like cell division. Pepperkok is working with Jan Ellenberg at EMBL in Heidelberg and Alvis Brazma at EMBL’s European Bioinformatics Institute (EMBL-EBI) in Hinxton, UK, to develop a public repository for such image-based screens, which others will be able to turn to when studying the function of human genes.

In cells where different genes are silenced (middle, bottom) the place where a component of the cell’s transport machinery (green) is located changes compared to normal cells (top).

written by Journal of Proteomics and Bioinformatics