Genetic diseases largely fall into two overarching camps. You have simple, single-gene alterations that produce a single, recognizable disease. And you have conditions like diabetes or cardiovascular disease, where many variations in many genes all make small contributions that fuel the illness.
Dyskeratosis congenita (DC) doesn’t fit either profile. While this rare genetic condition manifests in certain predictable ways (bone marrow failure among the most common), there is huge variability between patients. Yet genetics has revealed one common thread: the molecular caps that protect the ends of chromosomes, known as telomeres, are shortened in DC patients. This results in cells that age too quickly.
From there things get complicated, because problems with any of 11 different genes can trigger short telomeres in DC. And DC, it appears, is only the beginning.
Telomere diseases: None of these things look like the other
DC has been a mystery for decades. Historically, it was diagnosed based on three characteristic symptoms — unusual skin pigmentation patterns, nail discoloration and white patches in the mouth. However, with the discovery of genetic mutations, it’s become clear that only a minority of patients have that clinical profile.
The plot has thickened.
“DC is now recognized as a severe form of a remarkably broad spectrum of telomere diseases,” says Suneet Agarwal, MD, PhD, a pediatric hematologist/oncologist at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center. His lab published a study in Nature Genetics late last year investigating why the loss of gene #11, called PARN, can cause DC. “The genetic discoveries in DC have connected syndromes that can manifest in infancy with brain, eye, blood, bone and other problems to cancer or lung or liver disease in middle aged, ‘healthy’ individuals.”
CTC1: encodes a protein that regulates telomere repeat length
DKC1: encodes dyskerin, a protein in telomerase that binds and stabilizes TERC
NHP2: encodes a protein in telomerase that works with dyskerin to stabilize TERC
NOP10: encodes another protein in telomerase that works with dyskerin to stabilize TERC
PARN: encodes an enzyme that important for creation of TERC RNA
RTEL1: encodes a protein that modulates telomere DNA structure
TERT: encodes the critical enzyme of telomerase that adds repeats to telomeres
TERC: encodes the RNA template that TERT uses to add repeats to the telomere
TINF2: encodes TIN2, a protein that shields the telomere ends
WRAP53/TCAB1: encodes a protein that binds TERC to deliver telomerase to the right part of the nucleus
By and large, DC’s story is one of following the genetics, a process made easier through whole-genome and whole-exome sequencing. Some of the 11 genes linked to DC to date (see sidebar at right) make proteins that work on the telomere directly. Some of the others instead work on TERC, an RNA template for bases that are added to the end of the telomere.
PARN seems to fall into that latter camp. Until a U.K. research team reported PARN mutations in three DC patient families in early 2015, no one thought it played any role in telomere biology. But using induced pluripotent stem (iPS) cells generated from two DC patients with PARN mutations, Agarwal’s team made an unexpected connection.
It goes like this: The PARN enzyme helps cells process and stabilize newly-formed TERC RNA. Less PARN, less TERC; less TERC, less telomerase (the enzyme that elongates telomeres). Less telomerase, short telomeres.
“PARN was supposed to be a general factor that helps turn RNA over in a cell, getting rid of transcripts when they’re not needed,” Agarwal says. “But the discovery of PARN mutations in patients who clearly had telomere diseases demanded that we find a link. What we learned from studying patients’ cells is that if you mess with this enzyme, it most critically affects TERC. Our findings indicate that PARN is a potential target for manipulating telomerase in ways that could benefit patients.”
Telomere genetics: An ending still to be written
The range of genetic defects resulting telomere diseases isn’t fully known yet, as other diseases or “predispositions” due to short telomeres are sure to be lurking in the weeds. Case in point: The patients in whom Agarwal identified PARN deficits have two mutant copies of the gene, but even one mutant copy can predispose to disorders such as idiopathic pulmonary fibrosis, which affected both patients’ grandparents. And in one of those patients, part of the problem was a loss of PARN expression — not a mutation in the gene itself — suggesting problems with gene regulation.
“The genetic mutations we know about apply to some 70 percent of patients with DC,” Agarwal says. “But there will be other mutations and genetic variations that we don’t realize regulate telomere biology, and that have a important effect on human health. DC patients are providing an important biological connection.”