Dyskeratosis congenita and telomerase.
OBJECTIVE
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.


RESULTS
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.


CONCLUSIONS
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.
Bessler
Monica
M
Division of Hematology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA. mbessler@im.wustl.edu
Wilson
David B
DB
Mason
Philip J
PJ
D000818:Animals; D001483:Base Sequence; D018797:Cell Cycle Proteins / Q000235:genetics; D004195:Disease Models, Animal; D019871:Dyskeratosis Congenita / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics; D012313:RNA / Q000235:genetics; D019098:Telomerase / Q000235:genetics*
D018797:Cell Cycle Proteins; C112148:DKC1 protein, human; D009687:Nuclear Proteins; C422952:telomerase RNA; D012313:RNA; D019098:Telomerase