Using TERC to Tackle a Rare Disease

Aliya Ojuade
7 min readDec 28, 2020


Exploring how using a gene can treat Dyskeratosis Congenita.

Recap on Dyskeratosis Congenita

There are many ways to approach an anomaly. However, you could create the most deliberate, thought-out plan, and yet the results won’t always be as expected. Today, I’ll be exploring how this anomaly — Dyskeratosis Congenita — can be treated using just one gene and how this treatment will change the lives of many.

What Is DC?

Features of a patient with DC; Image: ResearchGate

Dyskeratosis Congenita (DC) is a rare, inherited form of bone marrow failure (BMF) with which the bone marrow cannot produce enough blood cells. Patients show signs of cracked/deformed nails, unusual web-like skin pigmentation, and white patches inside the mouth (demonstrated above).

DC increases the risk of developing life-threatening diseases, such as:

  1. Myelodysplastic Syndrome (when the blood cells don’t develop properly);
  2. Aplastic Anemia (when the body stops producing an adequate amount of blood cells);
  3. and Leukemia (or other types of cancer).

The most severe subsets of DC include Hoyeraal-Hreidarsson Syndrome (HH) and Revesz Syndrome (RS). With HH, patients experience intellectual disabilities. With RS, patients undergo BMF or exudative retinopathy. Almost all children with Hoyeraal-Hreidarsson Syndrome have died before the age of four. To learn more about HH and RS, check out my article.

Now, that all sounds pretty frightening. And patients aren’t given much of an opportunity with the only treatment options being:

  • Stem Cell Transplantation — which has a 10-year survival rate of just 23%.
  • Androgen Therapy — which uses steroid drugs that produce temporary results.

So what do you do when you’re pushed into an impossible position regarding a rare disease?

Easy. You turn to exogenous TERC.

Exploring TERC

Okay, that was a joke. But in this case, exogenous TERC could actually be a therapy option to treat Dyskeratosis Congenita. Here’s how.

What is TERC?

TERC stands for telomerase RNA component and is one of the two major components that work in the telomerase enzyme.

Great, now what’s telomerase? As cells divide, telomeres — the protective caps at the ends of chromosomes — shorten. When they reach a critical length, the cell dies (apoptosis). Telomerase, however, is an enzyme that adds a repeated DNA sequence (TTAGGG) to restore the length of telomeres so the cell can live for a longer period of time. It’s mainly active in cells that rapidly divide, and less active in regular somatic cells.

I created a simulation of a telomerase enzyme below.

Model of telomerase.

Each portion represents different genes. Focusing on this situation, the very bottom right (labeled 1) is where the gene Telomerase Reverse Transriptase (TERT) is located. The section labeled as 2 signifies the area where telomerase RNA is located.

So where does TERC tie into all of this? TERC works closely with TERT to maintain telomerase function. TERT adds the additional DNA sequence to the ends of telomeres. TERC produces hTR, which is an RNA molecule responsible for providing the template used to create the TTAGGG sequence. If this gene is impaired, the telomerase will not be able to perform its function.

Telomerase adding TTAGGG to telomeres. hTR produces the RNA template.


When a disease is autosomal dominant, it only requires one mutated gene from a parent to get the condition. A study found that families with autosomal dominant dyskeratosis congenita (AD-DC) all have similar mutations in the TERC gene. With Dyskeratosis Congenita, this leads to haploinsufficiency (when one copy of a gene is deleted/inactivated and the other copy isn’t enough to produce the gene’s product), a catalytic defect, or damaged RNA accumulation.

The study gathered 27 affected people with AD-DC from 8 families. Each of them had heterozygous mutations in TERC, meaning they inherited different forms of the gene from each parent. 7 out of the 12 affected parents were asymptomatic, and the disease was only diagnosed by identifying a TERC mutation.

Telomere length was investigated next. The study found that individuals with TERC mutations had a negative value for ΔTEL (change in telomere length), which indicates that they had significantly shorter telomeres than usual. Between parents and children with the mutation, the second generation had noticeably shorter telomeres compared to the first. In each family, the condition became more and more severe as the generations went on.

So what does this all mean? The study concluded that those with heterozygous TERC mutations may stay asymptomatic until adulthood, but the haploinsufficiency due to these mutations will cause Dyskeratosis Congenita. The severity of this condition increases as telomeres shorten through each generation. A TERC mutation is one of the main causes of DC.

The Experiment

In a situation like this one, scientists wondered if providing patients with outside (exogenous) TERC would make up for the mutation and improve the telomeres/telomerase.

In order to test this theory, they used primary T lymphocytes (T cells) and B‐lymphocyte (B cells) cell lines in their experiment. T lymphocytes are a major part of the immune system that attack foreign, infected, and/or cancer cells. B‐lymphocytes create antibodies that aid the body in fighting off infections.

Image: TheScientist

To get T lymphocytes samples, blood samples were collected from four DC patients and four healthy people. Two of the patients had TERC mutations, while the other two had DKC1 mutations (which is a gene that creates dyskerin — a protein responsible for maintaining telomere structure). Lymphoprep (a medium used to isolate mononuclear cells from cord blood, peripheral blood, and bone marrow) was used to separate the T cells. They were then incubated at 37°C overnight with the lentiviral supernatant, which provided time for transgene expression before 10ml of phytohaemagglutinin (PHA; a lectin from plants used for mitotic stimulation in lymphocytes) was added.

B‐lymphocyte lines (B-LCL) were acquired from samples of six DC patients and two healthy people. Two of these patients had DKC1 mutations, while the rest had TERC mutations. The procedure was similar to that for T cells.

In order to measure telomerase activity, the TRAPeze RT Telomerase Detection Kit was used. An Applied Biosystems 7500 Real-Time PCR Systems machine (pictured below) was used to measure fluorescent polymerase chain reaction (PCR).

An ABI 7500 real‐time PCR system.

eGFP (below) is an enhanced green fluorescent protein that, when exposed to blue light, displays a strong fluorescence. This was used in the experiment. To find the differences in telomerase activity with TERC and eGFP, a Student’s T-test was used. This test is a statistical hypothesis test used to determine if there’s a distinct difference between two sample groups.

T lymphocyte colonies magnified 400x (phase contrast microscopy — left); (fluorescence — right).

Using a subtelomeric probe from the arm of chromosome 7, telomere length was measured by Southern blot analysis (a technique used to detect specific DNA sequences). A Typhoon 9400 Variable Mode Imager and Imagequant TL v2005 software was used to visualize the Southern blots.

Typhoon 9400 Variable Mode Imager

Upon doing this experiment, they noticed that using exogenous TERC alone was able to increase telomerase activity in mutated T cells and B cell lines, as well as improve overall B cell line growth over an extended period of time. This implies that the TERC could be providing extra substrate for telomerase to function at its maximum turnover (catalyzation) rate. Basically, this means the TERC could speed up the time it takes for telomerase to perform its enzymatic reaction and take effect.

Final Words

Before experiments using exogenous genes to make up for mutations or damaged genes, those with diseases similar to DC were left with no hope. However, now that we’ve experimented with these types of treatments, it opens the window for countless new therapy options and many innovative cures. Before we know it, no one will have to suffer from Dyskeratosis Congenita or any other genetic condition.

Key Points

  • Dyskeratosis Congenita is a rare, inherited form of bone marrow failure with which the bone marrow cannot produce enough blood cells.
  • Families with autosomal dominant dyskeratosis congenita (AD-DC) all have similar mutations in the TERC gene.
  • TERC (telomerase RNA component) produces hTR, which is an RNA molecule responsible for providing the template used to create the TTAGGG sequence that telomerase adds to the ends of chromosomes.
  • By using exogenous (outside) TERC in DC patients, scientists discovered that it was able to increase telomerase activity in mutated T cells and B cell lines and improve overall B cell line growth over a long period of time.


A Quick Message

Before you leave, don’t forget to check out my Linkedin! Email me at or set up a meeting with further questions or comments — I’d love to hear from you!



Aliya Ojuade

16 - longevity/vr researcher - tks alumni