Gene Coding Error Associated with Rare Lung Disease
Idiopathic pulmonary fibrosis (IPF) is a rare disease of the lung, although it is the most common form of pulmonary fibrosis. Fibrosis refers to scarring and the scarring from IPF results in stiffness in the lung leading to difficulties in breathing. The symptoms are irreversible and progressive. Idiopathic refers to its cause being unknown, not related to smoking or other diseases.
Researchers with Johns Hopkins have identified a genetic abnormality in a single gene that is probably responsible for IPF and may have implications for other diseases of the telomeres, the short protective ends of chromosomes. They published their research in the journal Genes & Development.
The research group analyzed the DNA sequence of a patient with IPF and 13 of his relatives. They identified a coding error in the DNA sequence of the ZCCHC8 gene. The result of this error decreased production of a necessary protein by half. The protein is integral to maintaining the length of telomeres.
Each time a cell divides, telomeres grow a tiny bit shorter. Telomere shortening is related to aging, but problems with the molecular machinery that maintain telomeres are linked to a variety of diseases, including IPF, bone marrow failure, some liver diseases and myelodysplastic syndromes. Previous research showed that telomere length was useful for determining which medication to treat IPF with.
“Combining clinical and molecular approaches can be very powerful in efforts to understand the cause of genetic disease and its biology,” stated Mary Armanios, professor of oncology at the Johns Hopkins Kimmel Cancer Center and clinical director of the Telomere Center at Johns Hopkins. “We’re finding that there are many gene pathways that can disturb telomere length regulation.”
In the last 15 years, Armanios identified five of seven telomere-related genetic abnormalities in families with pulmonary fibrosis. This new discovery marks the eighth.
Armanios and her research team performed whole genome sequencing of the IPF patient and that person’s relatives. Some of the family members were found to have low levels of telomerase RNA component or TR. This is one of two molecular components of telomerase, the enzyme that functions to lengthen telomeres. Less TR, less telomerase, resulting in less ability to maintain and repair the telomeres.
They then analyzed the variations in the genomes among the family members with low TR levels and compared them to the genomes of those with normal levels. In the family members with abnormal areas of DNA, the group focused on a section of DNA on chromosome 12. That segment has 17 million base pairs. Previously, the ZCCHC8 gene was not known to be associated with telomere maintenance.
Armanios’s team measured the protein churned out by the abnormal ZCCHC8 gene and discovered that the people with low TR levels had half the amount of ZCCHC8 protein compared to the family members with normal TR levels.
The researchers then utilized CRISPR gene editing in human cells and mice to determine the function of the ZCCHC8 gene protein. What they found was the protein usually trims the ends of TRs, allowing them to mature and work as part of telomerase. But in those lacking ZCCHC8, there is an excess of untrimmed TRs, which can’t become part of telomerase.
Armanios believes the results could lead to new therapies that fix the balance of TRs in cells. It would likely have implications for research into other telomere diseases as well as aging.
“We’ve gone from knowing only a few gene errors associated with a small percentage of IPF cases a decade ago to understanding what contributes to more than a third of the families whose IPF gene had not been characterized and nearly 10% of other IPF cases,” Armanios said.