Dyskeratosis congenita and telomerase.

Abstract

Dyskeratosis congenita, a rare condition characterized by mucocutaneous abnormalities and bone marrow failure, is caused by inherited defects in the telomerase complex. Autosomal dominant dyskeratosis congenita is associated with mutations in the RNA component of telomerase, hTERC, while X-linked dyskeratosis congenita is due to mutations in the gene encoding dyskerin, a protein implicated in both telomerase function and ribosomal RNA processing. This review highlights recent research on dyskeratosis congenita and its relevance to other fields, including cancer and aging. Newly developed animal models suggest that defects in ribosomal RNA processing contribute to the phenotype of X-linked dyskeratosis congenita. Bone marrow dysfunction may be the first manifestation of dyskeratosis congenita in children, and hTERC mutations have been detected in a subset of patients presumed to have idiopathic aplastic anemia or myelodysplastic syndrome. In vitro studies suggest that hTERC mutations associated with dyskeratosis congenita or aplastic anemia either impair the specific activity of telomerase, decrease hTERC stability, or disrupt assembly of the telomerase complex. Recent clinical reports suggest that nonmyeloablative conditioning regimens afford better outcomes in patients with dyskeratosis congenita who require hematopoietic stem cell transplantation. Studies of dyskeratosis congenita have shed light on the pathobiology of aplastic anemia and other forms of bone marrow dysfunction. It seems likely that mutations in other genes involved in telomere maintenance will be linked to bone marrow failure or other human diseases. Genetic testing for occult dyskeratosis congenita may be warranted in selected patients with aplastic anemia or myelodysplastic syndrome, as this may impact the choice of therapies.