Inherited mutations in the helicase RTEL1 cause telomere dysfunction and Hoyeraal-Hreidarsson syndrome

Telomeres protect the ends of eukaryotic chromosomes. Telomeres shorten with age and serve as a biological clock that limits cell proliferation. Excessive telomere shortening accelerates aging, but telomere elongation may facilitate cancer. We found inherited mutations in the regulator of telomere elongation helicase 1 (RTEL1), which cause Hoyeraal-Hreidarsson syndrome, a fatal disease characterized by accelerated telomere shortening, immunodeficiency, and developmental defects. Introducing a normal RTEL1 gene into affected cells prevented telomere shortening and extended their lifespan in culture. The telomere defects, genomic instability, and growth arrest observed in RTEL1-deficient cells help in our understanding the central roles of telomeres in aging and cancer.