Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:


Gene Coding Error Found in Rare, Inherited Form of Lung-Scarring Disorder Linked to Short Telomeres


Genetic flaw may become part of a small but growing list of diagnostic markers for inherited 'short telomere' diseases

By combing through the entire genetic sequences of a person with a lung scarring disease and 13 of the person's relatives, Johns Hopkins Medicine researchers say they have found a coding error in a single gene that is likely responsible for a rare form of the disease and the abnormally short protective DNA caps on chromosomes long associated with it.

This is an image of human telomeres in cells. Each telomere is shown by red dots in resting nuclei of cells (circles) and cells that are dividing (separated linear chromosomes).

Credit: Mary Armanios

The error was found in the DNA sequence of the gene ZCCHC8, and it decreases by half the production of a protein needed to keep those caps -- called telomeres -- at a critical length, say the researchers. The finding, they add, means the flaw likely will become part of a small but growing list of diagnostic markers for so-called short telomere syndromes.

A report on the work, which focused on the disease known as idiopathic pulmonary fibrosis (IPF) was published online Sept. 5 in the journal Genes & Development.

"Combining clinical and molecular approaches can be very powerful in efforts to understand the cause of genetic disease and its biology," says Mary Armanios, M.D., 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." Over the past 15 years, Armanios has identified five of seven telomere-related genetic errors in families with pulmonary fibrosis. Now, there is an eighth, she says.

IPF occurs in approximately 100,000 people in the U.S., says Armanios, and creates lung scarring not attributed to smoking or other environmental factors. An estimated one in five people with IPF are thought to have a hereditary form of the disease, and half of those cases are linked to an inherited tendency for very short telomeres.

Telomeres protect the ends of chromosomal DNA like the plastic tubes on the ends of shoelaces, and they normally shorten with aging. Made up of repetitive sequences of DNA, normal telomeres have enough length to withstand the erosion that occurs over a normal lifespan. However, some people are born with abnormally short telomeres, causing problems with the cells' ability to divide and multiply, and leading to an assortment of disorders including IPF, bone marrow failure, some forms of liver disease and cancers of the bone marrow called myelodysplastic syndromes.

In previous research, Armanios showed that knowing whether a person with IPF has short telomeres is important to choose the right therapy. If short telomeres are involved, treatments for some disorders should include reduced doses of chemotherapy before bone marrow transplants, less use of immunosuppressant drugs, and use of lung and bone marrow transplant donors who don't have telomere-related genetic errors.

The gene errors that run in families with IPF are generally rare among populations, so they are difficult to pinpoint, says Armanios. "It's like looking for the proverbial needle in the haystack," she says. So, the researchers have to break the haystack apart and study the genetics of individual families to find the hereditary culprits.

To find the eighth mutation, they performed whole genome sequencing to examine the DNA sequences of a patient with IPF and 13 of the person's relatives. First, they found that some of the family members had low levels of telomerase RNA component, or TR. It's one of two biochemical pieces of telomerase, the enzyme that lengthens telomeres. With less TR, less telomerase is available to maintain, restore, and repair the DNA end caps.

Next, the researchers compared variations among the entire genome between family members with low TR levels and those with normal levels. Among the altered areas of DNA in family members with low TR levels, Armanios and her team narrowed their search to a section of DNA on chromosome 12 that is 17 million basepairs long (out of 3 billion basepairs in the human genome). Within this region, the gene ZCCHC8 had not previously been known to have functions related to telomere maintenance.

However, Armanios and her team measured the protein made by the error-containing ZCCHC8 gene and found that family members with low TR levels had half the amount of ZCCHC8 protein compared with family members who had normal TR amounts.

To determine the ZCCHC8 protein's function, Armanios' team used the gene editing technology CRISPR in human cells and mice to find that the protein typically trims the tail ends of TRs so that they can mature and function as part of telomerase. But cells and mice lacking ZCCHC8 have extra amounts of untrimmed TRs, resulting in a shorter version of the molecule that can no longer become part of telomerase.

Armanios says the findings could potentially reveal a way to develop therapies that restore the balance of TRs in cells to help with telomerase function.

Currently, physicians who suspect a person has a short telomere syndrome can undergo telomere length and genetic testing that includes the seven previously identified gene errors. Armanios says the ZCCHC8 gene error will be added to the diagnostic gene test.

"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," says Armanios.

The research was funded by the National Institutes of Health's National Cancer Institute (RO1CA225027, P30CA006973), National Heart, Lung and Blood Institute (RO1HL119476, T32HL007534, F32HL142207) and National Institute of General Medical Sciences (T32GM007309); the Maryland Cigarette Restitution Fund Program, the Commonwealth Foundation; the Gary Williams Foundation; the S&R Foundation Kuno Award; the Turock Scholars Fund; the National Science Foundation and P. Godrej.

Other members of the research team included Dustin L. Gable, Valeriya Gaysinskaya, Christine Atik, Conover Talbot Jr., Byunghak Kang, Susan Stanley, Elizabeth Pugh, Nuria Amat-Codina, Kara Schenk, Cory Brayton and Liliana Florea from Johns Hopkins, and Murat Arcasoy from Duke University School of Medicine.

DOI: 10.1101/gad.326785.119

Vanessa Wasta | EurekAlert!
Further information:

More articles from Health and Medicine:

nachricht Two commonly used uveitis drugs perform similarly in NIH-funded clinical trial
11.09.2019 | NIH/National Eye Institute

nachricht Innovative method provides unique insights into the structure of cells and tissues
10.09.2019 | University of Münster

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Graphene sets the stage for the next generation of THz astronomy detectors

Researchers from Chalmers University of Technology have demonstrated a detector made from graphene that could revolutionize the sensors used in next-generation space telescopes. The findings were recently published in the scientific journal Nature Astronomy.

Beyond superconductors, there are few materials that can fulfill the requirements needed for making ultra-sensitive and fast terahertz (THz) detectors for...

Im Focus: Physicists from Stuttgart prove the existence of a supersolid state of matte

A supersolid is a state of matter that can be described in simplified terms as being solid and liquid at the same time. In recent years, extensive efforts have been devoted to the detection of this exotic quantum matter. A research team led by Tilman Pfau and Tim Langen at the 5th Institute of Physics of the University of Stuttgart has succeeded in proving experimentally that the long-sought supersolid state of matter exists. The researchers report their results in Nature magazine.

In our everyday lives, we are familiar with matter existing in three different states: solid, liquid, or gas. However, if matter is cooled down to extremely...

Im Focus: World record for tandem perovskite-CIGS solar cell

A team headed by Prof. Steve Albrecht from the HZB will present a new world-record tandem solar cell at EU PVSEC, the world's largest international photovoltaic and solar energy conference and exhibition, in Marseille, France on September 11, 2019. This tandem solar cell combines the semiconducting materials perovskite and CIGS and achieves a certified efficiency of 23.26 per cent. One reason for this success lies in the cell’s intermediate layer of organic molecules: they self-organise to cover even rough semiconductor surfaces. Two patents have been filed for these layers.

Perovskite-based solar cells have experienced an incredibly rapid increase in efficiency over the last ten years. The combination of perovskites with classical...

Im Focus: A molecular 'atlas' of animal development

Researchers from the University of Pennsylvania provide a molecular map of every cell in a developing animal embryo

In a paper in Science this week, Penn researchers report the first detailed molecular characterization of how every cell changes during animal embryonic...

Im Focus: Next generation video: WDR and Fraunhofer HHI present significantly improved video quality at IFA 2019

The demand for even higher resolution videos will continue to increase in the coming years. For this reason, the German public service broadcaster WDR and the Fraunhofer Heinrich Hertz Institute HHI will collaborate in the coming months to test the Video Coding possibilities offered by the next international standard VVC/H.266.

VVC/H.266 is the successor standard to HEVC/H.265. The latter is currently the most modern and efficient standard for Video Coding and is used, for example, in...

All Focus news of the innovation-report >>>



Industry & Economy
Event News

Society 5.0: putting humans at the heart of digitalisation

10.09.2019 | Event News

Interspeech 2019 conference: Alexa and Siri in Graz

04.09.2019 | Event News

AI for Laser Technology Conference: optimizing the use of lasers with artificial intelligence

29.08.2019 | Event News

Latest News

Gene Coding Error Found in Rare, Inherited Form of Lung-Scarring Disorder Linked to Short Telomeres

11.09.2019 | Health and Medicine

Fraunhofer HHI shows latest video technologies at IBC 2019

11.09.2019 | Trade Fair News

Optical vacuum cleaner can manipulate nanoparticles

11.09.2019 | Physics and Astronomy

Science & Research
Overview of more VideoLinks >>>