title: Inherited bone marrow failure associated with germline mutation of ACD, the gene encoding telomere protein TPP1.
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.
authors.affiliation: Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA;
authors.forename: Yiran
authors.identifier: http://orcid.org/0000-0002-6549-8589
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Children's Medical Research Institute, Westmead, NSW, Australia; University of Sydney, Sydney, NSW, Australia;
authors.forename: Melissa
authors.initials: M
authors.lastname: Kartawinata
authors.affiliation: Beijing Genomics Institute-Shenzhen, Shenzhen, China;
authors.forename: Jiankang
authors.initials: J
authors.lastname: Li
authors.affiliation: Children's Medical Research Institute, Westmead, NSW, Australia; University of Sydney, Sydney, NSW, Australia;
authors.forename: Hilda A
authors.initials: HA
authors.lastname: Pickett
authors.affiliation: Haematology Department, Children's Hospital Westmead, Westmead, NSW, Australia;
authors.forename: Juliana
authors.initials: J
authors.lastname: Teo
authors.affiliation: Haematology Department, Children's Hospital Westmead, Westmead, NSW, Australia;
authors.forename: Tatjana
authors.initials: T
authors.lastname: Kilo
authors.affiliation: Children's Medical Research Institute, Westmead, NSW, Australia; University of Sydney, Sydney, NSW, Australia; Haematology Department, Children's Hospital Westmead, Westmead, NSW, Australia;
authors.forename: Pasquale M
authors.initials: PM
authors.lastname: Barbaro
authors.affiliation: 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;
authors.forename: Brendan
authors.initials: B
authors.lastname: Keating
authors.affiliation: Beijing Genomics Institute-Shenzhen, Shenzhen, China;
authors.forename: Yulan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA;
authors.forename: Lifeng
authors.identifier: http://orcid.org/0000-0003-1880-5811
authors.initials: L
authors.lastname: Tian
authors.affiliation: 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.
authors.forename: Ahmad
authors.initials: A
authors.lastname: Al-Odaib
authors.affiliation: Children's Medical Research Institute, Westmead, NSW, Australia; University of Sydney, Sydney, NSW, Australia;
authors.forename: Roger R
authors.identifier: http://orcid.org/0000-0002-6302-6107
authors.initials: RR
authors.lastname: Reddel
authors.affiliation: University of Sydney, Sydney, NSW, Australia; Western Sydney Genetics Program, Children's Hospital Westmead, Westmead, NSW, Australia.
authors.forename: John
authors.initials: J
authors.lastname: Christodoulou
authors.affiliation: Beijing Genomics Institute-Shenzhen, Shenzhen, China;
authors.forename: Xun
authors.initials: X
authors.lastname: Xu
authors.affiliation: 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;
authors.forename: Hakon
authors.initials: H
authors.lastname: Hakonarson
authors.affiliation: Children's Medical Research Institute, Westmead, NSW, Australia; University of Sydney, Sydney, NSW, Australia;
authors.forename: Tracy M
authors.identifier: http://orcid.org/0000-0002-7990-5501
authors.initials: TM
authors.lastname: Bryan
mesh_terms: D000328:Adult; D000483:Alleles; D000740:Anemia / Q000235:genetics; D001853:Bone Marrow / Q000473:pathology*; D001855:Bone Marrow Diseases / Q000235:genetics*; D002648:Child; D059472:Exome / Q000235:genetics; D005260:Female; D015894:Genome, Human / Q000235:genetics; D018095:Germ-Line Mutation / Q000235:genetics*; D006801:Humans; D040582:Inheritance Patterns / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics; D010375:Pedigree; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D057057:Serine Proteases / Q000235:genetics*; D000089804:Shelterin Complex; D019098:Telomerase / Q000235:genetics* / Q000378:metabolism; D016615:Telomere / Q000378:metabolism*; D059505:Telomere Homeostasis / Q000235:genetics; D034501:Telomere-Binding Proteins
chemical_list: C495876:ACD protein, human; D050505:Mutant Proteins; D012333:RNA, Messenger; D000089804:Shelterin Complex; D034501:Telomere-Binding Proteins; D019098:Telomerase; D057057:Serine Proteases