In a quiet corner of Ottawa, a research team spent three years chasing a question that weighed heavily on families of children born with a rare and often fatal disorder: what goes wrong inside the body's smallest machinery? Their answer points to an enzyme that folds DNA into order within human cells, and to the way a small inherited flaw in one gene can unravel its work. The discovery does not yet bring a cure, but it lifts a long-standing veil and gives future healers a clearer map of where the path begins.
Researchers Trace Rare Pediatric Disorder LIC Syndrome to Defects in a DNA Compaction Enzyme
LIC syndrome causes failure to thrive and immune deficiency in infants and can progress to fatal pediatric pulmonary disease in early childhood.
Nobody knew the biochemical cause for LIC syndrome. Now there's an answer.
Mark
Start with the basics. What did this team actually find?
Mimi
They showed how mutations in a gene called NSMCE3 disable an enzyme, the Smc5/6 complex, which cells use to compact DNA and repair chromosomes. That failure is tied to LIC syndrome in young children.
Mark
Why had nobody done this before?
Mimi
Nobody had managed to purify the human enzyme. D'Amours says his team built a new system to do it, and that opened the door to studying its structure.
Luke
Worth flagging that the claim of being first, and the claim of importance, come from D'Amours himself. We have his account, not an independent assessment.
Mark
Fair. What does the disease look like for families?
Mimi
Symptoms start in the first months of life: failure to thrive, immune deficiency, and in some children fatal lung disease in early childhood.
Mark
So does this mean a treatment is close?
Luke
No. Nothing here reports a therapy or a trial. D'Amours calls it a milestone on the way to treatments, which is a statement of direction, not of arrival.
Mimi
But it matters that before this, the biochemical cause was unknown. You can't aim a treatment without knowing what's broken.
Mark
And the modeling of the mutations?
Luke
They recreated the mutations in their own system and saw impaired chromosome repair. That is a lab model, so how closely it matches what happens in patients' bodies isn't established in what we have.
Der Puls
- A rare inherited disorder strikes infants within months of birth, leaving them failing to thrive while their immune defenses weaken.
- Tiny mutations in the NSMCE3 gene disrupt a DNA-compacting enzyme that cells rely on to keep their chromosomes intact.
- No one had ever purified the human version of this enzyme, so the team built an entirely new system to isolate it.
- Recreating the disease's mutations in the lab revealed how the enzyme loses its power to repair chromosomes, linking the disorder's name to its molecular root.
- The discovery opens a foundational route toward treatment, but no therapy has yet been reported and the next steps remain uncertain.
In a quiet corner of Ottawa, a research team spent three years chasing a question that weighed heavily on families of children born with a rare and often fatal disorder: what goes wrong inside the body's smallest machinery? Their answer points to an enzyme that folds DNA into order within human cells, and to the way a small inherited flaw in one gene can unravel its work. The discovery does not yet bring a cure, but it lifts a long-standing veil and gives future healers a clearer map of where the path begins.
For three years, Damien D'Amours and his team at the Ottawa Institute of Systems Biology pursued a question that families living with a rare childhood disorder had never been able to answer. What was going wrong, at the molecular level, in LIC syndrome? The team now believes it has found the answer, and it lies in an enzyme that compacts DNA inside human cells.
LIC stands for Lung disease, Immunodeficiency and Chromosome breakage. Symptoms appear in the first months of life. Infants often fail to thrive, their immune systems are weakened, and the illness can advance to fatal lung disease in early childhood. The cause is small inactivating mutations in NSMCE3, a gene that produces a factor essential to the cell nucleus.
The obstacle was that no one had ever purified the human form of the enzyme involved, the Smc5/6 complex. D'Amours's team built a new system to do it, the first to succeed. With the purified enzyme in hand, they could reveal its structure and show its ability to compact DNA, combining biophysics, genetics, proteomics and classical biochemistry.
When the researchers recreated the disease's mutations in their system, the enzyme's capacity to repair chromosomes was impaired. D'Amours describes this as the missing link between the disorder's name and its underlying cause. He credits the systems biology approach behind the institute for making the work possible, and calls the finding one of the most important milestones toward treating LIC patients.
Still, the work does not yet offer a therapy. No treatment has been reported, and the significance claimed so far comes from the lead researcher himself. The open question is whether understanding how the Smc5/6 complex fails can be turned into help for the children born with these mutations.
For three years, Damien D'Amours and his team at the Ottawa Institute of Systems Biology worked on a question that families affected by a rare childhood disorder had no answer to: what, at the molecular level, goes wrong in LIC syndrome? The team now says it has found the answer, and it lies in an enzyme that compacts DNA inside human cells.
LIC stands for Lung disease, Immunodeficiency and Chromosome breakage. The symptoms begin within the first few months after birth. Infants typically fail to thrive and have weakened immune systems, and the illness can progress to fatal pediatric pulmonary disease in early childhood. The condition is caused by small inactivating mutations in a gene called NSMCE3, which encodes a factor essential to the nucleus of human cells.
D'Amours is a Full Professor in the Department of Cellular & Molecular Medicine in the Faculty of Medicine at the University of Ottawa. His lab studies how cells divide and proliferate efficiently. In describing the work, he said the group found how defects in a kind of DNA compaction machine can cause the disorder. The machine is the Smc5/6 complex, an enzyme that plays a crucial part in keeping chromosomes intact.
The obstacle was that nobody had ever purified the human version of this enzyme. D'Amours says his team built a completely new system to do it, the first in the world to succeed. With purified enzyme in hand, they could reveal its structure and demonstrate its ability to compact DNA. They combined biophysics, advanced genetics, proteomics and classical biochemistry to do so.
The researchers then recreated the mutations that cause LIC syndrome in their system. According to D'Amours, those mutations impair the ability of the Smc5/6 complex to repair chromosomes in cells. That offers an explanation for how LIC mutations undermine a cell's capacity to maintain a healthy genome, and it connects the chromosome breakage in the disease's name to the underlying enzyme.
D'Amours credits the approach to systems biology, which uses large-scale genomics, proteomics and metabolomics technologies along with model organisms to understand disease at the level of whole systems. He pointed to the University of Ottawa's creation of the Ottawa Institute of Systems Biology as part of that shift, and said the institute's approach made the new purification system possible.
He describes the finding as one of the most important milestones on the way to devising treatments for LIC patients. His case rests on a gap that has now been filled: before this work, he says, nobody knew the biochemical cause of LIC syndrome or how the mutated enzyme affects the cells of affected children.
What the work does not yet offer is a therapy. No treatment has been reported, and the claims about the study's significance come from the lead researcher himself. The next step is whether understanding how the Smc5/6 complex fails can be turned into a way to help children born with these mutations.
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Prior to our work, nobody knew the biochemical cause for the LIC syndrome; we provided answers to these fundamental questions.— Damien D'Amours, University of Ottawa
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