APR 19, 2019 3:22 PM PDT

Rare Type of Genetic Mutation to Blame for Inherited Metabolic Disorder

WRITTEN BY: Carmen Leitch

Inherited metabolic disorders, in which the body is unable to break down a specific nutrient, are usually caused by an error in one gene and can cause a wide range of devastating health problems. Now an international team of researchers has found that a rare kind of genetic mutation, a repeat expansion, is to blame for three kinds of rare, undiagnosed conditions that affect children. These mutations are very challenging to identify; the whole genome has to be sequenced to reveal them because instead of a deleterious change in the sequence, the sequence is normal and nearby DNA is a few hundred times as long as it should be.

Image credit: Pixnio

"To detect this kind of DNA multiplication, you can only use whole-genome sequencing and have to search through billions of pieces of DNA; it's truly a search for the needle in the haystack," explained the lead author of the study Dr. Clara van Karnebeek. "With our new approach we have finally solved our mystery cases, and we now expect to find the genetic cause of other, as of yet unexplained, genetic metabolic diseases."

Repetitive expansions of DNA are connected to around thirty different diseases.

"For kids with rare diseases and their families, finding the root causes of their disorders is tremendously important," said Dr. Wyeth Wasserman, a co-author of the study. "A diagnosis gives us the potential to intervene, relieves undeserved parental guilt, and provides insights into more common diseases."

Once the disease is diagnosed, researchers can pursue potential treatment avenues. They may aim to repair the genetic dysfunction or supplement the impaired nutrient or missing enzyme. Any intervention that can slow the progression of damage can improve the quality of life for patients and their families.

The researchers had to take a new approach to reveal the causative problem. Genes contain sequences that code for protein, called exons. Many times, scientists will only check those areas that code for protein to look for errors that lead to disease.

"In our search, we focused on variations that would have been hard to discover through exome sequencing," said Drögemöller. "After months of experimenting with various different analyses, we finally uncovered this novel genetic variant by using new targeted approaches aimed at identifying DNA repeat expansions."

"These findings were made possible by a multidisciplinary approach and advances in technology, techniques, and software," said Richmond. "It wouldn't have been possible as recently as two years ago and, most importantly, it shows us what to look for in other undiagnosed cases."

This work showed that an enzyme that normally converts an amino acid called glutamine to a molecule called glutamate - glutaminase, is involved in this disease. The scientists still have to figure out whether the symptoms are arising because glutamine is accumulating, or glutamate is absent. Affected children experience serious delays in developmental and problems with speech, language, balance, and coordination. It is a rare problem, having been found in one of 8,000 people. However, taken together, rare diseases with an unknown cause have a significant impact on the lives of many people. 

"We can do better for children with rare diseases. For the 50 percent who can't find answers, this discovery and new approach will help us dig in and potentially find the causes of their disease," said Richmond.

The video above from the National Institutes of Health discusses tandem repeats in the mammalian genome.


Sources: AAAS/Eurekalert! via UBC, New England Journal of Medicine

About the Author
  • Experienced research scientist and technical expert with authorships on 28 peer-reviewed publications, traveler to over 60 countries, published photographer and internationally-exhibited painter, volunteer trained in disaster-response, CPR and DV counseling.
You May Also Like
APR 26, 2020
Genetics & Genomics
Does Poor Sleep Lead to Obesity, or is the Opposite True?
APR 26, 2020
Does Poor Sleep Lead to Obesity, or is the Opposite True?
For many years, researchers have been aware of the link between obesity and poor sleep or a lack of sleep. But what come ...
APR 28, 2020
Genetics & Genomics
Evolution Observed in Fish in a Single Generation
APR 28, 2020
Evolution Observed in Fish in a Single Generation
In a five year study, scientists have now shown that stickleback fish were able to alter some of their traits within a s ...
JUN 15, 2020
Genetics & Genomics
Genetic Variant Study Links Brain Cells to Multiple Sclerosis
JUN 15, 2020
Genetic Variant Study Links Brain Cells to Multiple Sclerosis
Multiple sclerosis (MS) is an autoimmune disorder, in which the immune system attacks an insulating sheath that coats ne ...
JUL 03, 2020
Genetics & Genomics
Why Can Old Mothers Keep Producing Offspring?
JUL 03, 2020
Why Can Old Mothers Keep Producing Offspring?
The children of older mothers tend to have fewer children and have higher mortality. So why is it still biologically pos ...
JUL 11, 2020
Genetics & Genomics
Cocaine Changes Gene Expression in a Specific Part of the Brain
JUL 11, 2020
Cocaine Changes Gene Expression in a Specific Part of the Brain
Scientists have begun to examine how cocaine exposure alters gene expression in a specific region of the brain, and the ...
JUL 24, 2020
Immunology
Telling the Difference Between Eczema and Psoriasis
JUL 24, 2020
Telling the Difference Between Eczema and Psoriasis
It can be extremely different even for professionals to tell the difference between psoriasis, an autoimmune disorder, a ...
Loading Comments...