Cause of rare type of dwarfism found

"This is the news I have been waiting for my whole life."

Monica Zaring, who has Saul-Wilson syndrome

4th October 2018

Single spontaneous gene change found to cause Saul-Wilson syndrome

A new study published today as part of the Scottish Genomes Partnership uncovers the cause of Saul-Wilson syndrome: an alteration in the gene involved in the cell’s protein packager, the Golgi complex.

First defined in 1990, only 15 cases of Saul-Wilson Syndrome are known worldwide and the cause of the syndrome—characterised by short stature, microcephaly (small head), hearing loss and early developmental delays—remained unknown until now.

For children born with a rare genetic disease and their parents, much of their lives are spent searching for answers. They undergo many medical tests as part of a 'diagnostic odyssey'.

“This is the news I have been waiting for my whole life,” says Monica Zaring, who has Saul-Wilson syndrome.

“I feel so grateful for all the doctors who never gave up, even when they didn’t have answers, and I hope this information will help more people in the future.”

Monica wrote about the new scientific discovery in her blog.

Photos via the Sanford Burnham Prebys Medical Discovery Institute

The research, which was published in the American Journal of Human Genetics (DOI: 10.1016/j.ajhg.2018.09.003) was an international collaboration involving clinicians and scientists in the USA, Scotland and Sweden.

In Scotland, the work was led by Professor Andrew Jackson and Dr David Parry (both at the MRC IGMM, University of Edinburgh).

Funding for sequencing and data storage for the Scottish part of the study was provided through the Scottish Genomes Partnership.

Other key members of the team are from

  • the Sanford Burnham Prebys Medical Discovery Institute in California

  • the National Human Genome Research Institute in Maryland

  • the University of Oregon

  • the Nemours/Alfred I. duPont Hospital for Children in Delaware

  • the Karolinksa Institutet in Stockholm.

“Children with Saul-Wilson syndrome and their parents live with many unanswered questions,” says Carlos Ferreira, medical geneticist at the National Human Genome Research Institute. “Knowing the underlying cause of the condition is a major step forward for these individuals and could help scientists find a treatment for the syndrome. This finding also advances our understanding of the genome and Golgi complex’s impact on human health, which may help us understand more skeletal disorders.”

Proteins, the workhorses of our body, are transported inside of our cells via packages called vesicles. These packages travel from one cellular organ, the endoplasmic reticulum (ER), to the Golgi complex, which resembles a stack of pancakes. Keeping the Golgi in working order relies on a protein complex called COG, which has eight subunits.

“The Golgi complex is where proteins ‘get ready for the dance’,” says co-first author Zhijie Xia, postdoctoral researcher in the laboratory of Hudson Freeze, co-senior author of the paper and director and professor of the Human Genetics Program at Sanford Burnham Prebys Medical Discovery Institute. “Here, proteins are modified in a variety of ways—such as sugars being added or removed—which affects their ultimate function in the body.”

Using the latest genetic technology, the team of scientists analysed 14 people with Saul-Wilson syndrome. All the individuals had the very same change in just one copy of the gene that codes for COG4 protein, which is part of the Golgi complex. This change in the COG4 gene arose spontaneously (de novo), meaning each parent did not have the mutation. As a result, one amino acid, the building block of proteins, was swapped for another. Specifically, glycine was replaced by arginine.

Further study revealed that in the cells of people with Saul-Wilson syndrome, packages of proteins moved slowly from the ER to the Golgi complex, but then rapidly returned—similar to a delivery truck that drives slowly to your home but speeds back to the warehouse. The size of the Golgi complex was halved. The scientists also found the Golgi complex’s ability to add sugars to one protein, decorin, was altered. This protein travels out of the cell and helps support the collagen in skin.

© 2020 Scottish Genomes Partnership

Scottish Genomes Partnership gratefully acknowledges the funding received from the Chief Scientist Office of the Scottish Government Health Directorates and the Medical Research Council Whole Genome Sequencing for Health and Wealth Initiative.