Discovery of gene silencer offers hope for autosomal dominant leukodystrophy

A team led by University of Pittsburgh School of Public Health geneticists has shown, for the first time, that a gene "silencer" that resides in junk DNA is directly sparing people from a devastating and fatal progressive neurological disease.

The discovery, published in Nature Communications, explains why not all people with the genetic mutation develop the disease – called autosomal dominant leukodystrophy (ADLD) – and has significant implications for diagnosis and genetic counseling. It also explains why the mutation only affects one type of cell, despite being expressed in most cells in the body.

The function of gene silencers is only now being understood and, in this case, it is allowing us to tell some patients who previously would have been given a fatal prognosis that they will not die of a cruel and debilitating disease. Our discovery also explains the mystery of why a gene duplication expressed in most cells of the body could result in a disease that only affects one type of cell."

Quasar Padiath, M.B.B.S., Ph.D., senior author, professor and chair of Pitt Public Health's Department of Human Genetics

ADLD is a fatal, adult onset, progressive neurological disease that affects a few thousand patients worldwide. Previously, Padiath identified that people with ADLD have an extra copy of the gene lamin B1. This triggers the loss of myelin – the insulating material around nerves that allows them to rapidly conduct pulses. Symptoms, which include muscle weakness, seizures and cognitive decline, typically present around age 40 to 50.

The "silencer" discovery was made following a happenstance conversation between Padiath and a geneticist in a neighboring office at Pitt Public Health.

"My colleague knew I was researching the lamin B1 gene and mentioned that a collaborator of his had a patient with a duplication of that gene, so he asked if I would mind talking with them," said Padiath. "Imagine – of 30,000 or so possible human genes, his collaborator's patient had a mutation in the one gene I was studying. That patient started this entire study."

Padiath consulted on the case and found that the patient carried the mutation that duplicated the lamin B1 gene, but did not exhibit demyelination or symptoms of the disorder. He then found two other families with the mutation but not the disorder.

Using sophisticated genetics tools, including CRISPR gene editing, novel mouse models and artificial intelligence-based computational approaches, Padiath and his team identified a genetic element in the non-coding – or "junk DNA" – region of the genome. They found that the element physically interacts with lamin B1 gene and silences its expression – but only in specific cells in the central nervous system called oligodendrocytes. Those cells produce myelin.

The silencer regulates the expression of the lamin B1 gene and is present in all individuals with normal myelination. People with ADLD have a duplication of the lamin B1 gene without the silencer – and that results in demyelination and disease symptoms. But an unknown number of people who have the mutation that causes the duplication of the lamin B1 gene also have a duplication of the silencer – and they never develop the disease.

"We have no way of knowing exactly how many people are walking around with this gene duplication, but don't know it because they also have the silencer duplication," Padiath said. "We'd only find out if they happened to get genetic testing – potentially for reasons completely unrelated to concerns about ADLD – and the results flagged that they have the duplication."

If a patient's genetic testing is positive for ADLD, genetic counselors can now do an extra step to see if they also have the silencer duplication and, potentially, reassure them that they will not develop symptomatic disease. Beyond that immediate outcome, Padiath says the discovery could have implications for a variety of demyelinating diseases, such as multiple sclerosis.

"Geneticists are only now starting to uncover the importance of junk DNA and reveal that it can directly influence the coding regions of the genome through silencing and enhancing actions," Padiath said. "This has the potential to lead to a better understanding of a variety of rare – and common – genetic diseases and point the way to new therapies."

Additional authors of this research – who are from across the U.S. and around the world, including the United Kingdom, Portugal, Brazil, Saudi Arabia, Canada and Sweden – are listed in the Nature Communications manuscript.

This research was funded by National Institutes of Health grants R01R01NS126193, R21NS131906, R33NS104384, R33NS106087 and R01NS095884 and ADLD Center grant ADLD-23-001-02, along with additional funding listed in the study manuscript.