First-ever look at potentially deadly metabolic disorder that strikes infants

August 31, 2017
A 3-D view of dolichylphosphomannose. Credit: DPMS

You may have never heard of congenital disorder of glycosylation, but parents whose children are born with forms of this rare – and underreported – metabolic disorder know all too well the dangers they pose, including developmental delay, failure to thrive, stroke-like symptoms, seizures and cerebellar dysfunction.

Often serious, and sometimes fatal, CDG diseases are hereditary disorders that affect a complex metabolic process, known as glycosylation, which is critical for the development of organs. Reporting in the journal Nature Communications, researchers from KTH Royal Institute of Technology in Stockholm have demonstrated for the first time the way in which certain types of CDG diseases arise from the shortage of a fundamental building block for proteins, the enzyme dolichylphosphomannose, which is known as DPMS.

Glycosylation produces sugar chains that are attached to the surface of proteins. The majority of proteins produced in the human body, about two thirds, undergo the maturation process to become glycoproteins. A glycoprotein obtains its final shape and function once the are in place.

Although there is yet no cure for CDG, the researchers in Sweden have given us an unprecedented look at the inner workings of DPMS. KTH Biotechnology Professor Christina Divne says the team hope that their work will lead to improved chances of predicting and treating CDG.

The article in Nature Communication details how the team determined the three-dimensional atomic structure of DPMS, using a technically-advanced and time-consuming method.

"From the very 3-D image of the enzyme's appearance, we have managed to determine how it functions; and by that explain why disease-causing variants of DPMS lack the ability to produce the necessary building block, and therefore cause disease," Divne says.

The study also sheds new light on how aberrant DPMS causes severe psychomotor developmental delays, microcephaly, epileptic seizures, and sometimes body malformations. A connection has also been found to certain forms of cancer.

First identified in 1980, CDG cases have been documented in limited numbers. Divne says that many cases are likely unrecorded since a correct diagnosis requires that the sequences for known disease genes be determined – a step that is not regularly performed. Diagnosis also requires knowledge of relevant genetic variants.

"CDG diseases are often misdiagnosed and mistaken for other disease states," she says. "The symptoms resemble those of many other neurometabolic diseases and physicians do not always know what they are looking for."

She says that genetic variants that cause CDG most likely occur at a considerably higher frequency than what can be observed in a population. Most CDG diseases cause severe disabilities, and probably lead to premature death of the fetus and spontaneous abortion. "A spontaneously aborted fetus rarely ends up at a hospital to be gene tested," she notes.

About 120 different glycosylation disorders are currently known, a number that has increased threefold in 10 years, and there are probably many more to be discovered, she says. In a Canadian study on patients examined for unexplained developmental retardation, more than 10 percent could be traced to genetic defects in glycosylation processes.

Explore further: Phenotype varies for presumed pathogenic variants in KCNB1

More information: Rosaria Gandini et al. Structural basis for dolichylphosphate mannose biosynthesis, Nature Communications (2017). DOI: 10.1038/s41467-017-00187-2

Related Stories

Phenotype varies for presumed pathogenic variants in KCNB1

August 16, 2017
(HealthDay)—De novo KCNB1 missense and loss-of-function variants are associated with neurodevelopmental disorders, with or without seizures, according to a study published online Aug. 14 in JAMA Neurology.

A kidney disease's genetic clues are uncovered

March 6, 2017
Researchers have uncovered new genetic clues to understanding IgA nephropathy (IgAN), or Berger's disease, an autoimmune kidney disease and a common cause of kidney failure. The findings are relevant to IgAN as well as other ...

Holy glycosylation! New 'bat signal' flags distressed cells in childhood genetic diseases

June 12, 2012
Just as Gotham City uses the Bat Signal to call for Batman's aid, a new tool developed by scientists from the Sanford-Burnham Medical Research Institute in La Jolla, California, should serve as the cellular equivalent for ...

Research team identifies new genetic syndrome

March 4, 2014
Researchers at the National Institutes of Health (NIH) have identified a new genetic syndrome characterized by a constellation of health problems, including severe allergy, immune deficiency, autoimmunity and motor and neurocognitive ...

Genetic defect may confer resistance to certain viral infections

April 9, 2014
A National Institutes of Health (NIH) study reports that a rare genetic disease, while depleting patients of infection-fighting antibodies, may actually protect them from certain severe or recurrent viral infections. Researchers ...

Recommended for you

A math concept from the engineering world points to a way of making massive transcriptome studies more efficient

November 17, 2017
To most people, data compression refers to shrinking existing data—say from a song or picture's raw digital recording—by removing some data, but not so much as to render it unrecognizable (think MP3 or JPEG files). Now, ...

US scientists try first gene editing in the body

November 15, 2017
Scientists for the first time have tried editing a gene inside the body in a bold attempt to permanently change a person's DNA to try to cure a disease.

Genetic mutation in extended Amish family in Indiana protects against aging and increases longevity (Update)

November 15, 2017
The first genetic mutation that appears to protect against multiple aspects of biological aging in humans has been discovered in an extended family of Old Order Amish living in the vicinity of Berne, Indiana, report Northwestern ...

Genetic variant prompts cells to store fat, fueling obesity

November 13, 2017
Obesity is often attributed to a simple equation: People are eating too much and exercising too little. But evidence is growing that at least some of the weight gain that plagues modern humans is predetermined. New research ...

Discovering a protein's role in gene expression

November 10, 2017
Northwestern Medicine scientists have discovered that a protein called BRWD2/PHIP binds to histone lysine 4 (H3K4) methylation—a key molecular event that influences gene expression—and demonstrated that it does so via ...

Twin study finds genetics affects where children look, shaping mental development

November 9, 2017
A new study co-led by Indiana University that tracked the eye movement of twins finds that genetics plays a strong role in how people attend to their environment.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.