Impaired telomere maintenance in Alazami syndrome patients with LARP7 deficiency

BMC Genomics

Research

Hirotoshi Hoshiyama¹  Ning Zhang¹  Brody Holohan¹  Wanil Kim¹  Tsung-Po Lai¹  Woodring E. Wright¹  Jerry W. Shay²  Anas M. Alazami³  Fowzan S. Alkuraya⁴  M. Stephen Meyn⁵ 

[1] Department of Cell Biology, University of Texas Southwestern Medical Center, 75390, Dallas, TX, USA;Department of Cell Biology, University of Texas Southwestern Medical Center, 75390, Dallas, TX, USA;Center for Excellence in Genomics Medicine Research, King Abdulaziz University, Jeddah, Saudi Arabia;Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia;Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia;Department of Anatomy and Cell, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia;Department of Pediatrics, King Khalid University Hospital and College of Medicine, King Saud University, Riyadh, Saudi Arabia;The Hospital for Sick Children, Department of Pediatric and Molecular Genetics, University of Toronto, M5s1A8, Toronto, ON, Canada;

关键词: Idiopathic Pulmonary Fibrosis;    Telomere Length;    Short Telomere;    Telomere Maintenance;    Telomere Repeat Amplification Protocol;   

DOI  :  10.1186/s12864-016-3093-4

来源: Springer

【 摘 要 】

BackgroundLoss of function in genes required for telomere maintenance result in disorders known as telomeropathies, which are characterized by a pattern of symptoms including generalized and specific lymphocytopenias as well as very short telomere length and disease anticipation.MethodsBecause human LARP7 is the most likely ortholog of the Tetrahymena p65 protein, which is required for telomerase activity in that organism, we investigated the effects of LARP7 silencing in human cells as well as in two distinct families with Alazami syndrome (loss of function of LARP7).ResultsDepletion of LARP7 caused a reduction in telomerase enzymatic activity and progressively shorter telomeres in human cancer cell lines. Alazami syndrome patients from two separate cohorts exhibited very short lymphocyte telomeres. Further, wild-type offspring of LARP7 mutant individuals also had very short telomeres, comparable to what is observed in telomerase (hTERT) mutant cohorts.ConclusionsTogether, these experiments demonstrate that in addition to the readily apparent developmental disorder associated with LARP7 deficiency, an underlying telomeropathy exists even in unaffected siblings of these individuals.

【 授权许可】

CC BY   
© The Author(s). 2016