Luis F. Zirnberger Batista, Ph.D.
Inherited mutations in genes controlling telomere homeostasis underlie Dyskeratosis congenita (DC), a disease of impaired tissue maintenance resulting in bone marrow failure, pulmonary fibrosis, epidermal defects and cancer predisposition. The severity of DC and its age of onset vary widely. Although the basis for this variation is unclear, it seems to depend in part on the mode of inheritance and the specific genes involved. DC can be presented in autosomal dominant (mutations in TERT, the telomerase reverse transcriptase and TERC, the telomerase RNA component), autosomal recessive (i.e. mutations in the recently described TCAB1) and X-linked (mutations in DKC1, a telomerase protein that binds TERC) forms. Individuals with autosomal dominant (AD) and autosomal recessive (AR) commonly present with milder disease at more advanced ages than those with the X-linked disease. Due to difficulties in purifying stem cells from patients and maintaining them in the laboratory, tissue stem cells from DC patients have not been directly studied. Additionally, the endogenous telomerase enzyme complex has never been studied in stem cells or progenitor cells from DC patients. With the aim of creating a new model to study DC and gain new insights in telomerase biology, we have recently reprogrammed wild-type and DC primary fibroblasts to an induced pluripotent stem cell (iPSC) state. This approach can provide important new insights into the relationship between genotype and phenotype in human diseases with diverse modes of inheritance.