Biochemists confirm existence of theoretical genetic disorder

January 8, 2018, Bielefeld University
By studying the cell cultures, Dr. Björn Kowalewski and Mai-Britt Ilse confirmed that the patient's mutated gene has lost it function. Credit: Bielefeld University

Thanks to the sequencing of the human genome, scientists can now discover potential disorders for which there are no known patients. One such disorder is MPS III-E, originally also called Dierks's disorder after its discoverer. Doctors at the Hadassah-Hebrew University Medical Center in Jerusalem (Israel) found consistent symptoms of progressive blindness in three patient families that indicated the presence of a previously unknown genetic defect. Genomic analyses at the University of Lausanne (Switzerland) delivered a candidate gene on which Professor Dr. Thomas Dierks from Bielefeld University had already published a research article in 2012. Studies by Dierks' research team now revealed that these patients indeed suffer from MPS III-E. The researchers are now presenting their analysis in the journal Genetics in Medicine.

Through biochemical studies and genetic analyses, it was finally possible to confirm the disorder in five from the Israeli families. "These persons have increasingly poor vision due to progressive retinal atrophy. They also develop an inner ear hearing impairment," reports Dierks. "These are the same symptoms—alongside others—that we also found among mice in our earlier studies."

The scientists at Bielefeld had studied the disorder in mice. In these animals, they switched off the gene responsible for producing the arylsulfatase G. This ensured that the carbohydrate could no longer be fully degraded. "As a result, the carbohydrate accumulated in the cells," explains Thomas Dierks. This accumulation takes place in the lysosomes, the 'recycling plants' of the cells. Due to this metabolic dysfunction, the breakdown also of other substances such as lipids and proteins gradually comes to a standstill. The accumulation then increases the size of the lysosome until it destroys the cell—and that brings about the disorder.

To determine whether the mutated gene in the patients actually does lead to the enzyme defect, Dierks' team studied the patient gene in a cell culture. This culture produced the enzyme (arylsulfatase G). They found that "the enzyme actually was seriously damaged. It is unable to break down the heparan sulfate," says Dierks.

The researchers were surprised the first time they found out about the Israeli patients in April. "They did not start to show the symptoms before the age of 40. Based on our studies with mice, we assumed that the symptoms would emerge much earlier—perhaps after ten years," says Dierks. His explanation for this delay in the outbreak of the disorder is that large parts of the heparan sulfate molecule can be degraded without arylsulfatase G. "Hence, it takes more time to accumulate."

Now that the cause of the symptoms is known, it is possible to think about an for the patients. "The required enzyme can be produced biotechnologically with the help of cell cultures," says Dierks. For the treatment, the enzyme is injected intravenously. It is then carried through the body in the blood and should break down the heparan sulfate in the tissues. "However, the brain is hard for the enzyme to reach. Moreover, the disorder has to be diagnosed through gene tests before the symptoms appear if treatment is to commence before damage has become irreparable." Now that the symptoms resulting from this hereditary disorder in humans are known, Dierks expects that the genetic defect will also be diagnosed in more people. "Further patients should be found particularly among the unexplained cases with Usher syndrome—this indicates a combined loss of vision and hearing."

Explore further: Controlling the amount of heparan sulphate – a carbohydrate needed for foetal development

More information: Samer Khateb et al, A homozygous founder missense variant in arylsulfatase G abolishes its enzymatic activity causing atypical Usher syndrome in humans, GENETICS in MEDICINE (2018). DOI: 10.1038/gim.2017.227

Related Stories

Controlling the amount of heparan sulphate – a carbohydrate needed for foetal development

September 2, 2016
Heparan sulphate occurs as carbohydrate chains which are very important for human body cells both for normal foetal development and during the course of various diseases. All new molecular knowledge concerning these chains ...

New gene therapy targets brain disorders

November 9, 2017
UNSW researchers have tailored gene therapy for a rare genetic disorder called Canavan disease, and say it could eventually be adapted to treat other inherited disorders affecting the brain.

New biomarker found for group of rare metabolic diseases

August 7, 2017
A newly discovered biomarker associated with a rare metabolic disorder may facilitate better diagnosis and identification of new drugs for clinical trials for the disease, according to researchers in the Perelman School of ...

Complex mechanisms in Gaucher disease unravelled

March 30, 2017
Gaucher disease is a genetic disorder of lipid metabolism. Sphingosine, a compound as enigmatic as the sphinx, plays a key role in this metabolic disorder. Scientists from the Bonn research center caesar have identified some ...

Research supports newborn screening and early treatment for rare genetic disorder, MPS I

December 1, 2010
In a study that supports the need for newborn screening and early treatment for a rare genetic disorder, researchers at Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center (LA BioMed) and Iowa State University ...

New inhibitor has potential as cancer drug

October 22, 2007
Laboratory experiments have previously shown that cancer cells overproduce an enzyme, heparanase, which splits the body’s own polysaccharide heparan sulfate into shorter fragments. The amount of enzyme is related to the ...

Recommended for you

Scientists identify critical cancer immunity genes using new genetic barcoding technology

October 20, 2018
Scientists at Mount Sinai have developed a novel technology for simultaneously analyzing the functions of hundreds of genes with resolution reaching the single cell level. The technology relies on a barcoding approach using ...

A single missing gene leads to miscarriage

October 19, 2018
A single gene from the mother plays such a crucial role in the development of the placenta that its dysfunction leads to miscarriages. Researchers from the Medical Faculty of Ruhr-Universität Bochum (RUB) have observed this ...

Making gene therapy delivery safer and more efficient

October 18, 2018
Viral vectors used to deliver gene therapies undergo spontaneous changes during manufacturing which affects their structure and function, found researchers from the Perelman School of Medicine at the University of Pennsylvania ...

Student develops microfluidics device to help scientists identify early genetic markers of cancer

October 16, 2018
As anyone who has played "Where's Waldo" knows, searching for a single item in a landscape filled with a mélange of characters and objects can be a challenge. Chrissy O'Keefe, a Ph.D. student in the Department of Biomedical ...

Researchers use brain cells in a dish to study genetic origins of schizophrenia

October 16, 2018
A study in Biological Psychiatry has established a new analytical method for investigating the complex genetic origins of mental illnesses using brain cells that are grown in a dish from human embryonic stem cells. Researchers ...

Why heart contractions are weaker in those with hypertrophic cardiomyopathy

October 16, 2018
When a young athlete suddenly dies of a heart attack, chances are high that they suffer from familial hypertrophic cardiomyopathy (HCM). Itis the most common genetic heart disease in the US and affects an estimated 1 in 500 ...

1 comment

Adjust slider to filter visible comments by rank

Display comments: newest first

not rated yet Jan 13, 2018
12,000 diseases - oops, sorry 12,001. Looks like possibly "NATURAL death could be on the way out" - until of course medicine works through the list, - this does beg the question "what the hell was god doing with all that time before creation?" Working on a tan?

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.