Scientists show how mutation causes incurable premature aging disease

October 31, 2016
This stylistic diagram shows a gene in relation to the double helix structure of DNA and to a chromosome (right). The chromosome is X-shaped because it is dividing. Introns are regions often found in eukaryote genes that are removed in the splicing process (after the DNA is transcribed into RNA): Only the exons encode the protein. The diagram labels a region of only 55 or so bases as a gene. In reality, most genes are hundreds of times longer. Credit: Thomas Splettstoesser/Wikipedia/CC BY-SA 4.0

Scientists have demonstrated how a mutation in a specific protein in stem cells causes an incurable premature aging disease called dyskeratosis congenita, and were able to introduce the mutation into cultured human cells using gene editing technology.

The study findings provide a drug target for the disease, said lead study author Jayakrishnan Nandakumar, assistant professor of molecular, cellular and developmental biology at the University of Michigan.

The mutation compromises the function of an enzyme known as telomerase, which fuels stem cell division, he said. Stem cells must divide to repair old tissue.

This mutation, which occurs in the telomere protein TPP1, causes to slow or stop dividing in people with this rare, incurable disease. This can cause tissue breakdown, premature aging, bone marrow failure, cancer and even death.

Nandakumar and his U-M colleagues are believed to be the first to use genome editing technology called CRISPR/CAS9 to introduce a mutation into .

This gene editing technology is often described as a pair of molecular scissors, because it cuts DNA in precise locations to allow for additions, deletions and replacements of DNA near the cut. The acronyms stand for Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) and CRISPR-associated (CAS9).

The patient relevant to the study had one mutant gene, but also one normal TPP1 gene, yet still suffered from the disease. Nandakumar's group wanted to know if introducing one copy of the mutant TPP1 gene into cultured human cells using the CRISPR/CAS9 gene editing technology would compromise telomerase function in those cells, too.

It did, which meant that the mutation caused the disease.

"We envision that correcting the mutation in the stem cells of the patient will reverse the cellular symptoms of the disease, if and when such technology becomes available," Nandakumar said.

Understanding how the TPP1 mutation works also has implications for treating cancer patients, he said. This is because while the TPP1 mutation inhibits stem cell division in people with dyskeratosis congenita, normal TPP1 fuels in people with cancer.

The study, "Structural and functional consequences of a in the telomere protein TPP1," appears online in the Proceedings of the National Academy of Sciences the week of Oct. 31.

Explore further: Disease decoded: Gene mutation may lead to development of new cancer drugs

More information: Structural and functional consequences of a disease mutation in the telomere protein TPP1, Proceedings of the National Academy of Sciences,
www.pnas.org/cgi/doi/10.1073/pnas.1605685113

Related Stories

Scientists edit gene mutations in inherited form of anemia

October 26, 2016

A Yale-led research team used a new gene editing strategy to correct mutations that cause thalassemia, a form of anemia. Their gene editing technique provided corrections to the mutations and alleviated the disease in mice, ...

Genome engineering paves the way for sickle cell cure

October 12, 2016

A team of physicians and laboratory scientists has taken a key step toward a cure for sickle cell disease, using CRISPR-Cas9 gene editing to fix the mutated gene responsible for the disease in stem cells from the blood of ...

Scientists use stem cells to create HIV resistance

June 10, 2014

(Medical Xpress)—Yuet Wai Kan of the University of California, San Francisco and colleagues have created HIV-resistant white blood cells by editing the genomes of induced pluripotent stem cells. The researchers inserted ...

Recommended for you

Gene may hold key to hearing recovery

April 24, 2017

Researchers have discovered that a protein implicated in human longevity may also play a role in restoring hearing after noise exposure. The findings, where were published in the journal Scientific Reports, could one day ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.