title: A POT1 mutation implicates defective telomere end fill-in and telomere truncations in Coats plus.
abstract: Coats plus (CP) can be caused by mutations in the CTC1 component of CST, which promotes polymerase α (polα)/primase-dependent fill-in throughout the genome and at telomeres. The cellular pathology relating to CP has not been established. We identified a homozygous POT1 S322L substitution (POT1(CP)) in two siblings with CP. POT1(CP)induced a proliferative arrest that could be bypassed by telomerase. POT1(CP)was expressed at normal levels, bound TPP1 and telomeres, and blocked ATR signaling. POT1(CP)was defective in regulating telomerase, leading to telomere elongation rather than the telomere shortening observed in other telomeropathies. POT1(CP)was also defective in the maintenance of the telomeric C strand, causing extended 3' overhangs and stochastic telomere truncations that could be healed by telomerase. Consistent with shortening of the telomeric C strand, metaphase chromosomes showed loss of telomeres synthesized by leading strand DNA synthesis. We propose that CP is caused by a defect in POT1/CST-dependent telomere fill-in. We further propose that deficiency in the fill-in step generates truncated telomeres that halt proliferation in cells lacking telomerase, whereas, in tissues expressing telomerase (e.g., bone marrow), the truncations are healed. The proposed etiology can explain why CP presents with features distinct from those associated with telomerase defects (e.g., dyskeratosis congenita).
authors.affiliation: The Rockefeller University, New York, New York 10065, USA;
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Takai
authors.affiliation: Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, Manchester Academic Health Sciences Centre, University of Manchester, Manchester M13 9PT, United Kingdom;
authors.forename: Emma
authors.initials: E
authors.lastname: Jenkinson
authors.affiliation: The Rockefeller University, New York, New York 10065, USA;
authors.forename: Shaheen
authors.initials: S
authors.lastname: Kabir
authors.affiliation: Department of Pediatrics, Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario M5G 1Z5, Canada;
authors.forename: Riyana
authors.initials: R
authors.lastname: Babul-Hirji
authors.affiliation: Department of Pediatrics, Division of Opthalmology and Visions Sciences, The Hospital for Sick Children, University of Toronto, Toronto, Ontario M5G 1Z5, Canada;
authors.forename: Nasrin
authors.initials: N
authors.lastname: Najm-Tehrani
authors.affiliation: The Prenatal Diagnosis and Medical Genetics Program, Department of Obstetrics and Gynecology, Mount Sinai Hospital, University of Toronto, Toronto, Ontario M5G 1X5, Canada; Department of Paediatrics, Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario M5G 1Z5, Canada;
authors.forename: David A
authors.initials: DA
authors.lastname: Chitayat
authors.affiliation: Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, Manchester Academic Health Sciences Centre, University of Manchester, Manchester M13 9PT, United Kingdom; UMR 1163, Institut National de la Santé et de la Recherche Médicale, Laboratory of Neurogenetics and Neuroinflammation, Paris Descartes-Sorbonne Paris Cité University, Institut Imagine, Hôpital Necker, Paris 75015, France.
authors.forename: Yanick J
authors.initials: YJ
authors.lastname: Crow
authors.affiliation: The Rockefeller University, New York, New York 10065, USA;
authors.forename: Titia
authors.initials: T
authors.lastname: de Lange
mesh_terms: D000626:Aminopeptidases / Q000378:metabolism; D001259:Ataxia / Q000235:genetics*; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism; D001932:Brain Neoplasms / Q000235:genetics*; D002114:Calcinosis / Q000235:genetics*; D002478:Cells, Cultured; D020863:Central Nervous System Cysts / Q000235:genetics*; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000378:metabolism; D005260:Female; D006801:Humans; D056784:Leukoencephalopathies / Q000235:genetics*; D008677:Metaphase; D009128:Muscle Spasticity / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D011485:Protein Binding; D012164:Retinal Diseases / Q000235:genetics*; D012640:Seizures / Q000235:genetics*; D057057:Serine Proteases / Q000378:metabolism; D000089804:Shelterin Complex; D015398:Signal Transduction; D016615:Telomere / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D059505:Telomere Homeostasis / Q000235:genetics; D059506:Telomere Shortening / Q000235:genetics*; D034501:Telomere-Binding Proteins / Q000235:genetics*
chemical_list: C495876:ACD protein, human; C544945:Ctc1 protein, human; C440849:POT1 protein, human; D000089804:Shelterin Complex; D034501:Telomere-Binding Proteins; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D057057:Serine Proteases; D000626:Aminopeptidases; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases
keywords: CST; CTC1; Coats plus; Exo1; POT1; telomerase; telomere