Corporate Banner
Satellite Banner
Genomics
Scientific Community
 
Become a Member | Sign in
Home>News>This Article
  News
Return

Genetic Disorder Causing Strokes, Vascular Inflammation in Children Discovered

Published: Thursday, February 20, 2014
Last Updated: Thursday, February 20, 2014
Bookmark and Share
NIH researchers have identified gene variants that cause a rare syndrome of sporadic fevers, skin rashes and recurring strokes, beginning early in childhood.

The team’s discovery coincides with findings by an Israeli research group that identified an overlapping set of variants of the same gene in patients with a similar type of blood vessel inflammation.

The NIH group first encountered a patient with the syndrome approximately 10 years ago. The patient, then 3 years old, experienced fevers, skin rash and strokes that left her severely disabled. Because there was no history of a similar illness in the family, the NIH group did not at first suspect a genetic cause, and treated the patient with immunosuppressive medication. However, when the NIH team evaluated a second patient with similar symptoms two years ago — a child who had experienced recurrent fevers and six strokes by her sixth birthday — they began to suspect a common genetic cause and embarked on a medical odyssey that has led not only to a diagnosis, but to fundamental new insights into blood vessel disease.

In their study, which appears in the Feb. 19, 2014, advance online edition of the New England Journal of Medicine, the researchers describe how next-generation genome sequencing, only recently available, facilitated a molecular diagnosis for patients in their study. The researchers found that harmful variants in the CECR1 gene impede production of a protein vital to the integrity of healthy blood vessel walls.

“This discovery is another example of genome sequencing playing a central role in revealing the genomic basis for an important rare disease,” said Eric D. Green, M.D., Ph.D., director of the National Human Genome Research Institute (NHGRI), where the lead members of the research team are based. “Such studies illustrate how genomics is paving the way to improved human health.”

The researchers showed that faulty variants in their patients’ DNA that encode the CECR1 gene cause a loss of function of the gene’s ability to produce of an enzyme called adenosine deaminase 2 (ADA2). Without it, abnormalities and inflammation in blood vessel walls result. The researchers call the new syndrome, deficiency of ADA2, or DADA2. The enzyme ADA2 is chemically similar to the enzyme ADA1, whose deficiency results in severe combined immunodeficiency disease.

NHGRI Scientific Director Daniel Kastner, M.D., Ph.D., led the team of collaborators from NIH and beyond in mounting the study of nine patients. “It has been incredibly fantastic to see this kind of progress being made within the last decade,” he said. “Our study raises the possibility that the ADA2 pathway may contribute to susceptibility to stroke in the more general population.”

For children, as with adults, stroke can affect physical, cognitive and emotional functioning. Some outcomes, such as blindness and deafness, can be lasting; others, such as the ability to walk, can be relearned.

“While no other incidence of this condition occurred in the families who came to our clinic, the early age of onset suggested to us that the patients were born with a genetic condition,” Dr. Kastner said. “We used a whole-exome screen to locate genetic variants in each of the patients.”

Whole-exome sequencing determines the order of DNA bases for the 1 percent of the human genome that codes for proteins. Qing Zhou, Ph,D., a post-doctoral fellow in Dr. Kastner’s lab, methodically analyzed two of the patients’ exomes as well as exomes of their parents. Among hundreds of variants that distinguished each patient from their parents, they located two variants that are novel or rare in the CECR1 gene, which encodes ADA2. These variants were passed from both parents to the affected child. The whole-exome sequence of a third patient identified another harmful variant of CECR1 in addition to a small genomic deletion that shuts down the second copy of the gene. They needed only a sequence reading of that single gene to confirm that three other patients were affected by harmful variants in this gene. Three of the eight detrimental variants that eliminate the protein ADA2 were shared among the first six patients.

The team subsequently sequenced the CECR1 gene in three additional patients from Turkey who had some of the symptoms of the new syndrome. They found that a homozygous pair — a double dose of a different variant — from the one detected in the first six patients causes a disease called polyarteritis nodosa (PAN). PAN is a form of vasculitis, an inflammation of medium and small arteries that leads to pain, rashes, numbness, weakness and vital organ damage. PAN can cause kidney failure, heart attack and stroke.

“We now know that this mutation exists in the Middle East and in Pakistani populations and that it is not that uncommon,” said Ivona Aksentijevich, M.D., senior author and staff scientist in NHGRI's Inflammatory Diseases Section. The Israeli researchers, whose study is published concurrently in the journal, found the same mutation in CECR1 as those NIH patients with PAN. The patients in the Israeli study are from families that emigrated to Israel from the country of Georgia. “This is the first time a single gene has been discovered that is involved in causing a system-wide form of vasculitis.” Dr. Aksentijevich said.

The researchers found data from a study of adult patients showing that those who carry only one mutation in this gene may have a predisposition to develop adult onset stroke. They also induced ADA2 deficiency in a zebrafish animal model. They found that zebrafish embryos that produce less ADA2 than normal embryos have cerebral bleeds, similar to those seen in some of the children with ADA2 deficiency. The primary role for ADA2 protein is as a growth factor. Data from the zebrafish model suggest that this growth factor plays a role in blood vessel development.

Members of the research team led by Manfred Boehm, M.D., senior investigator at the National Heart, Lung, and Blood Institute, established the link between ADA2 deficiency and inflammatory blood vessel disease in the patients. Dan Yang, M.D., Ph.D., a staff scientist in Dr. Boehm’s lab, discovered that ADA2 deficiency causes a faulty function in a subset of white blood cells called monocytes/macrophages. The faulty monocyte/macrophages attack the patients’ own blood vessels, resulting in a vicious circle of vessel damage and inflammation that leads to stroke and other blood vessel-related problems.

The discovery of the molecular basis of DADA2 has treatment implications. As an alternative to high doses of steroids, which produce profound side effects, the study suggests that treatment may include specialized drugs that inhibit inflammatory proteins produced during the syndrome. Also, since ADA2 is made in the bone marrow and circulates in the blood stream, the team is evaluating a way to replace ADA2 that is missing in the bloodstreams of those affected by DADA2. The researchers obtained approval from the Food and Drug Administration to test the safety and efficacy of using freshly frozen plasma to restore ADA2 functionality for treated patients. Alternatively, an artificial form of the protein would help, but is not currently in development. Bone marrow transplantation or genetic manipulation of bone marrow could also have a role in the treatment of these patients.

“This genome sequencing study expands what has previously been known about vascular biology, and it is truly gratifying to be among two labs using next-generation genome sequencing technology to arrive at complementary conclusions about the functionality of the same gene,” said Dr. Kastner. “The role of ADA2 in such serious human disease is important and suggests that ADA2 variants may contribute to other more common illnesses.”

The collaboration that brought the discovery of this new syndrome to light included researchers from NHGRI and five additional NIH institutes, including the National Heart, Lung, and Blood Institute; the National Institute of Allergy and Infectious Diseases; the National Institute of Arthritis and Musculoskeletal and Skin Diseases; the National Cancer Institute; and the National Institute of Diabetes and Digestive and Kidney Diseases, as well as the NIH Clinical Center.

NHGRI is one of the 27 institutes and centers at the NIH, an agency of the Department of Health and Human Services. The NHGRI Division of Intramural Research develops and implements technology to understand, diagnose and treat genomic and genetic diseases. 


Further Information

Join For Free

Access to this exclusive content is for Technology Networks Premium members only.

Join Technology Networks Premium for free access to:

  • Exclusive articles
  • Presentations from international conferences
  • Over 3,000+ scientific posters on ePosters
  • More than 4,500+ scientific videos on LabTube
  • 35 community eNewsletters


Sign In



Forgotten your details? Click Here
If you are not a member you can join here

*Please note: By logging into TechnologyNetworks.com you agree to accept the use of cookies. To find out more about the cookies we use and how to delete them, see our privacy policy.

Related Content

Submissions Open for the Cancer Moonshot Program
NCI opens online platform to submit ideas about research for Cancer Moonshot.
Tuesday, April 19, 2016
NIH Sequences Genome of a Fungus
Researchers at the Institute have sequenced genome of human, mouse and rat Pneumocystis that cause life-threatening Pneumonia in immunosuppressed hosts.
Tuesday, April 12, 2016
Decoding Ties Between Vascular Disease, Alzheimer’s
NIH consortium uses big data, team science to uncover complex interplay of factors.
Tuesday, March 15, 2016
Researchers Find Link Between Death of Tumor-Support Cells and Cancer Metastasis
Researchers at NIH have found that the lifespan of supportive cells in a tumor may control the spread of cancer.
Tuesday, February 23, 2016
Tick Genome Reveals Secrets of a Successful Bloodsucker
NIH-funded study could lead to new tick control methods.
Tuesday, February 09, 2016
Genomic Signature Shared by Five Types of Cancer
National Institutes of Health researchers have identified a striking signature in tumor DNA that occurs in five different types of cancer.
Monday, February 08, 2016
Cancer Drug Target Visualized at Atomic Resolution
New study using cryo-electron microscopy shows how potential drugs could inhibit cancer.
Thursday, February 04, 2016
Genome-Wide Study Yields Markers of Lithium Response
An international consortium of scientists has identified a stretch of chromosome that is associated with responsiveness to the mood-stabilizing medication lithium among patients with bipolar disorder.
Monday, February 01, 2016
Schizophrenia’s Strongest Known Genetic Risk Deconstructed
Suspect gene may trigger runaway synaptic pruning during adolescence – NIH-funded study.
Thursday, January 28, 2016
NIH Genome Sequencing Program Targets the Genomic Bases of Common, Rare Disease
The National Institutes of Health will fund a set of genome sequencing and analysis centers whose research will focus on understanding the genomic bases of common and rare human diseases.
Friday, January 15, 2016
Three Glaucoma-Related Genes Discovered
NIH-funded genetics analysis of glaucoma is largest to date.
Tuesday, January 12, 2016
International Study Reveals New Genetic Clues to AMD
NIH-funded research provides framework for future studies of AMD biology, therapy.
Tuesday, December 22, 2015
Dementia Linked to Deficient DNA Repair
Mutant forms of breast cancer factor 1 (BRCA1) are associated with breast and ovarian cancers but according to new findings, in the brain the normal BRCA1 gene product may also be linked to Alzheimer’s disease.
Tuesday, December 01, 2015
Batten Disease may Benefit from Gene Therapy
NIH-funded animal study suggests one-shot approach to injecting genes.
Friday, November 13, 2015
NIH Researchers Link Single Gene Variation to Obesity
Variation in the BDNF gene may affect brain’s regulation of appetite, study suggests.
Saturday, October 31, 2015
Scientific News
Known Genetic Risk Factors for Endometrial Cancer Doubles
An international collaboration of researchers has identified five new gene regions that increase a woman’s risk of developing endometrial cancer, one of the most common cancers to affect women, taking the number of known gene regions associated with the disease to nine.
Monovar Drills Down Into Cancer Genome
Rice, MD Anderson develop program to ID mutations in single cancer cells.
Autism, Cancer Share a Remarkable Number of Risk Genes
Researchers with the UC Davis Comprehensive Cancer Center, MIND Institute identify more than 40 common genes.
Number Of Known Genetic Risk Factors For Endometrial Cancer Doubled
An international collaboration of researchers has identified five new gene regions that increase a woman’s risk of developing endometrial cancer, one of the most common cancers to affect women, taking the number of known gene regions associated with the disease to nine.
Genetic Variant May Help Explain Why Labradors Are Prone To Obesity
A genetic variation associated with obesity and appetite in Labrador retrievers – the UK and US’s favourite dog breed – has been identified by scientists at the University of Cambridge. The finding may explain why Labrador retrievers are more likely to become obese than dogs of other breeds.
How Scientists Use DNA to Track Disease Outbreaks
They’re the top questions on everyone’s mind when a new disease outbreak happens: where did the virus come from? When did this happen? How long has it been spreading in a particular country or group of people?
Genetic Risk Factors of Disparate Diseases Share Similar Biological Underpinnings
Penn Institute for Biomedical Informatics and colleagues identify "roadmap" of disease mechanisms to identify candidate drug targets.
Stem Cells Know How to Unwind
Research led by the Babraham Institute with collaborators in the UK, Canada and Japan has revealed a new understanding of how an open genome structure supports the long-term and unrestricted developmental potential in embryonic stem cells.
Childhood Asthma Research Receives $2M
Research into the impact of a child’s upbringing and social and physical environments on the development of asthma will receive $2 million to tackle the condition that affects as many as one in three Canadians.
Five New Breast Cancer Genes Found
Discovery of mutations paves the way for personalised treatment of breast cancer.
Skyscraper Banner

SELECTBIO Market Reports
Go to LabTube
Go to eposters
 
Access to the latest scientific news
Exclusive articles
Upload and share your posters on ePosters
Latest presentations and webinars
View a library of 1,800+ scientific and medical posters
3,000+ scientific and medical posters
A library of 2,500+ scientific videos on LabTube
4,500+ scientific videos
Close
Premium CrownJOIN TECHNOLOGY NETWORKS PREMIUM FOR FREE!