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

  • Blood. 2014 Oct 30;124(18):2767-74. doi: 10.1182/blood-2014-08-596445.
Yiran Guo  1 ,  Melissa Kartawinata  2 ,  Jiankang Li  3 ,  Hilda A Pickett  2 ,  Juliana Teo  4 ,  Tatjana Kilo  4 ,  Pasquale M Barbaro  5 ,  Brendan Keating  6 ,  Yulan Chen  3 ,  Lifeng Tian  1 ,  Ahmad Al-Odaib  7 ,  Roger R Reddel  2 ,  John Christodoulou  8 ,  Xun Xu  3 ,  Hakon Hakonarson  6 ,  Tracy M Bryan  2
Affiliations
  • 1. Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA;
  • 2. Children's Medical Research Institute, Westmead, NSW, Australia; University of Sydney, Sydney, NSW, Australia;
  • 3. Beijing Genomics Institute-Shenzhen, Shenzhen, China;
  • 4. Haematology Department, Children's Hospital Westmead, Westmead, NSW, Australia;
  • 5. Children's Medical Research Institute, Westmead, NSW, Australia; University of Sydney, Sydney, NSW, Australia; Haematology Department, Children's Hospital Westmead, Westmead, NSW, Australia;
  • 6. Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA; Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA;
  • 7. University of Sydney, Sydney, NSW, Australia; Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia; and Western Sydney Genetics Program, Children's Hospital Westmead, Westmead, NSW, Australia.
  • 8. University of Sydney, Sydney, NSW, Australia; Western Sydney Genetics Program, Children's Hospital Westmead, Westmead, NSW, Australia.
PMID: 25205116 DOI: 10.1182/blood-2014-08-596445
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.