Mutation in ZCCHC8 Gene Linked to Short Telomeres and IPF Development, Study Suggests

A mutation in the gene ZCCHC8 leads to abnormalities in the structure of telomeres, the protective caps at the end of the DNA, leading to the development of idiopathic pulmonary fibrosis (IPF), a new study shows.

The study, titled “ZCCHC8, the nuclear exosome targeting component, is mutated in familial pulmonary fibrosis and is required for telomerase RNA maturation,” was published in the journal Genes and Development.

Telomeres occur at the end of DNA chromosomes and serve as a protection mechanism against DNA damage. They are composed of repetitive DNA sequences. While telomeres normally shorten as a person ages, regular telomeres have enough length to withstand the shortening that occurs over a normal lifespan.

However, some people are born with short telomeres, which can manifest itself in various diseases, including IPF. Thus, there is a subset of patients with IPF due to mutations in proteins that are responsible for the maintenance of telomeres. One such protein is an enzyme called telomerase, which helps synthesize and lengthen telomeres.

Telomerase is made up of two essential components: telomerase reverse transcriptase (TERT), and a specialized RNA molecule known as TR, which provides the template for telomere repeat addition. If there is less TERT or TR, there consequently is less telomerase available for maintaining telomeres.

Among families with IPF, about half carry mutations in their TERT or TR, and the rest carry mutations in other telomere maintenance genes.

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Researchers from Johns Hopkins University studied the family of an adult with IPF who had classic short telomere syndrome, and genetically lower levels of TR. To determine the genetics of the patient’s family, the researchers analyzed 13 of the individual’s family members.

Upon sequencing their DNA, the researchers found a mutation in the ZCCHC8 gene. Family members with low TR levels had half the amount of ZCCHC8 protein, compared with family members with normal TR levels.

In order to determine the purpose of ZCCHC8 in the maintenance of telomeres, the researchers performed an array of experiments.

First, they deleted the ZCCHC8 gene in cells. The team found that deletion led to an accumulation of immature TR, which could no longer function appropriately as part of the telomerase complex.

Next, the investigators generated mice that had a complete deletion of the ZCCHC8 gene (Zcchc8−/− mice). These mice were found to develop progressive and fatal neurodevelopmental problems. Gene expression in their brains was highly dysregulated, and showed accumulation and misprocessing of other types of RNAs.

Further analysis indicated that ZCCHC8 trims the tail ends of TRs, so that they can mature and function as part of the telomerase complex.

Thus, in mice and cells that lack ZCCHC8, there are large amounts of untrimmed TRs, resulting in a longer version of the molecule that can no longer become part of telomerase.

“Our data identify a novel cause of human short telomere syndromes-familial pulmonary fibrosis,” the researchers said.

According to the team, these results can have an impact on how patients are treated. Previous studies have suggested that IPF patients with short telomeres should be given a different therapeutic regimen compared with someone with normal telomere length.

“Combining clinical and molecular approaches can be very powerful in efforts to understand the cause of genetic disease and its biology,” Mary Armanios, MD, professor of oncology at the Johns Hopkins Kimmel Cancer Center, and clinical director of the Telomere Center at Johns Hopkins, said in a press release.

“We’re finding that there are many gene pathways that can disturb telomere length regulation,” Armanios concluded.

So far, according to the team, seven telomere-related genetic errors in families with pulmonary fibrosis have been identified. Now, ZCCHC8 will be added to this list, becoming the eight genetic error identified.