1. Inherited bone marrow failure associated with germline mutation of ACD, the gene encoding telomere protein TPP1.
- Author
-
Yiran Guo, Kartawinata, Melissa, Jiankang Li, Pickett, Hilda A., Juliana Teo, Tatjana Kilo, Barbara, Pasquale M., Keating, Brendan, Yulan Chen, Lifeng Tian, Al-Odaib, Ahmad, Reddel, Roger R., Xun Xu, John, Hakonarson, Hakon, and Bryan, Tracy M.
- Subjects
- *
BONE marrow diseases , *GERM cells , *TELOMERASE , *TELOMERES , *CARRIER proteins , *DNA damage - Abstract
Telomerase is a ribonucleoprotein enzyme that is necessary for overcoming telomere shortening in human germ and stem cells. Mutations in telomerase or other telomere-maintenance proteins can lead to diseases characterized by depletion of hematopoietic stem cells and bone marrow failure (BMF). Telomerase localization to telomeres requires an interaction with a region on the surface of the telomere-binding protein TPP1 known as the TEL patch. Here, we identify a family with aplastic anemia and other related hematopoietic disorders in which a 1-amino-acid deletion in the TEL patch of TPP1 (AK170) segregates with disease. All family members carrying this mutation, but not those with wild-type TPP1, have short telomeres. When introduced into 293T cells, TPP1 with the AK170 mutation is able to localize to telomeres but fails to recruit telomerase to telomeres, supporting a causal relationship between this TPP1 mutation and bone marrow disorders. ACDTTPP1 is thus a newly identified telomere-related gene in which mutations cause aplastic anemia and related BMF disorders. [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
- View/download PDF