Mice and DKC patients share a genetic deficiency that shortens their telomeres, the caps that protect the ends of each chromosome; studying how the mice recover normal telomere length could lead to novel treatments for this genetic disorder
The human genetic disease dyskeratosis congenita (DKC) is an autosomal dominant disease that leads to abnormalities in tissues with a rapid cell turnover - the skin, nails, bone marrow, lungs and gut. Patients with DKC experience life-threatening symptoms. Bone marrow failure increases their risk of fatal infections and cancer. Many die before the age of 30 and management of the disease is limited to trying to treat its symptoms.
At the heart of DKC is telomerase, the enzyme that maintains the length of telomeres, the protective caps on the ends of chromosomes. Telomerase has two main components; telomerase reverse transcriptase (TERT) and telomerase RNA. The latter is the template that TERT uses to produce telomere-extending DNA. Patients with DKC have a mutation in one TERT allele and under produce telomerase. This leads to a failure to maintain normal telomere length. Once the chromosomes erode beyond a certain point, they start to rearrange and cells show increasing genomic instability followed by cell death and tissue malfunction.
"DKC is one of the few examples in which there is a clear link between a genetic mutation that directly affects telomerase function and human disease," comments senior author Lea Harrington (Ontario Cancer Institute, Toronto, ON, Canada). "Teasing out the difference between cause and effect is a challenge."
mTert mice, which have one functional TERT allele and one disrupted allele, also show telomere shortening and represent a useful model for DKC. Research with this mouse model now aims to determine the potential for adaptive extension of telomeres. The underlying mechanisms could suggest novel therapies for DKC and could lead to methods of blocking telomerase inhibition in normal tissues during cancer therapy, so improving treatment efficacy.
"mTert mice provide an appropriate model for DKC that we can use to examine the long term consequences of TERT deficiency over several generations in a controlled setting," explains Harrington.