Inherited bone marrow failure associated with germline mutation of ACD, the gene encoding telomere protein TPP1

• Published in: Blood Vol. 124; no. 18; pp. 2767 - 2774
• Main Authors: Guo, Yiran, Kartawinata, Melissa, Li, Jiankang, Pickett, Hilda A., Teo, Juliana, Kilo, Tatjana, Barbaro, Pasquale M., Keating, Brendan, Chen, Yulan, Tian, Lifeng, Al-Odaib, Ahmad, Reddel, Roger R., Christodoulou, John, Xu, Xun, Hakonarson, Hakon, Bryan, Tracy M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 30-10-2014; American Society of Hematology
• Series: Hematopoiesis and Stem Cells
• Subjects: Adult; Alleles; Aminopeptidases - genetics; Anemia - genetics; Base Sequence; Bone Marrow - pathology; Bone Marrow Diseases - genetics; Child; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases - genetics; Exome - genetics; Family; Female; Genome, Human - genetics; Germ-Line Mutation - genetics; Humans; Inheritance Patterns - genetics; Male; Middle Aged; Molecular Sequence Data; Mutant Proteins - metabolism; Neoplasms - genetics; Pedigree; Phenotype; Plenary Paper; Protein Transport; RNA, Messenger - genetics; RNA, Messenger - metabolism; Serine Proteases - genetics; Telomerase - metabolism; Telomere - metabolism; Telomere Homeostasis - genetics
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2014-08-596445

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.
•Bone marrow failure can derive from germline mutation of the telomere protein TPP1 that is involved in recruiting telomerase to telomeres.•The observed mutation disrupts recruitment of telomerase to telomeres and segregates with short telomere length and disease phenotype.