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Engineered telomere degradation models dyskeratosis congenita

¹ Laboratory for Cell Biology and Genetics, The Rockefeller University, New York, New York 10065, USA; ² Department of Dermatology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390, USA; ³ Pathology and Laboratory Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA

Dyskeratosis congenita (DC) is an inherited bone marrow failure syndrome characterized by cutaneous symptoms, including hyperpigmentation and nail dystrophy. Some forms of DC are caused by mutations in telomerase, the enzyme that counteracts telomere shortening, suggesting a telomere-based disease mechanism. However, mice with extensively shortened telomeres due to telomerase deficiency do not develop the characteristics of DC, raising questions about the etiology of DC and/or mouse models for human telomere dysfunction. Here we describe mice engineered to undergo telomere degradation due to the absence of the shelterin component POT1b. When combined with reduced telomerase activity, POT1b deficiency elicits several characteristics of DC, including hyperpigmentation and fatal bone marrow failure at 4–5 mo of age. These results provide experimental support for the notion that DC is caused by telomere dysfunction, and demonstrate that key aspects of a human telomere-based disease can be modeled in the mouse.

[Keywords: Bone marrow failure; dyskeratosis congenita; POT1; shelterin; telomere; telomerase]

Received March 28, 2008; revised version accepted April 29, 2008.

⁵ Max Planck Institute of Molecular Cell Biology and Genetics, Pfotenhauerstrasse 108, 01307 Dresden, Germany.

⁶ Corresponding author.

E-MAIL delange{at}mail.rockefeller.edu; FAX (212) 327-7147.

Supplemental material is available at http://www.genesdev.org.

Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.1679208.

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