1. Inherited bone marrow failure associated with germline mutation of ACD, the gene encoding telomere protein TPP1
- Author
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Hakon Hakonarson, Juliana Teo, Yiran Guo, Xun Xu, Jiankang Li, Yulan Chen, Tatjana Kilo, Melissa Kartawinata, Tracy M. Bryan, Roger R. Reddel, Hilda A. Pickett, Lifeng Tian, Ahmad Al-Odaib, Brendan J. Keating, John Christodoulou, and Pasquale M Barbaro
- Subjects
Adult ,Male ,Telomerase ,Molecular Sequence Data ,Telomere-Binding Proteins ,Immunology ,Plenary Paper ,Inheritance Patterns ,Biology ,Biochemistry ,Shelterin Complex ,Telomerase RNA component ,Germline mutation ,Bone Marrow ,Neoplasms ,medicine ,Humans ,Exome ,Telomerase reverse transcriptase ,RNA, Messenger ,Aplastic anemia ,Child ,Bone Marrow Diseases ,Alleles ,Germ-Line Mutation ,Genome, Human ,Telomere Homeostasis ,Anemia ,Cell Biology ,Hematology ,Middle Aged ,Telomere ,medicine.disease ,Molecular biology ,Pedigree ,Phenotype ,medicine.anatomical_structure ,Cancer research ,Mutant Proteins ,Female ,Bone marrow ,Serine Proteases ,Dyskeratosis congenita - 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 (ΔK170) 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 ΔK170 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. ACD/TPP1 is thus a newly identified telomere-related gene in which mutations cause aplastic anemia and related BMF disorders.
- Published
- 2014