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Title: Functional interaction between compound heterozygous TERT mutations causes severe telomere biology disorder.
Austin Authors: Niaz, Aram;Truong, Jia Quyen;Manoleras, Annabel;Fox, Lucy;Blombery, Piers;Vasireddy, Raja S;Pickett, Hilda A;Curtin, Julie A;Barbaro, Pasquale M;Rodgers, Jonathan;Roy, John;Riley, Lisa G;Holien, Jessica K;Cohen, Scott B;Bryan, Tracy
Affiliation: Rare Diseases Functional Genomics, Kids Research, The Children's Hospital at Westmead and Children's Medical Research Institute, Westmead, NSW, Australia..
School of Science, STEM (Science, Technology, Engineering, and Mathematics) College, Royal Melbourne Institute of Technology (RMIT), Bundoora, VIC, Australia..
Children's Medical Research Institute, Faculty of Medicine and Health, University of Sydney, Westmead, NSW, Australia..
Department of Pathology, Peter MacCallum Cancer Center, Melbourne, VIC, Australia..
Clinical Haematology
Transfusion Research Unit, School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia..
Department of Medicine, University of Melbourne, Melbourne, VIC, Australia..
Clinical Haematology, Peter MacCallum Cancer Center/Royal Melbourne Hospital, Melbourne, VIC, Australia..
Haematology Department, Children's Hospital at Westmead, Westmead, NSW, Australia..
Children's Health Queensland and University of Queensland, South Brisbane, QLD, Australia..
Genetic Health Queensland, Royal Brisbane and Women's Hospital, Herston, QLD, Australia.
Child and Adolescent Health, University of Sydney, Sydney, NSW, Australia..
Issue Date: 28-Jun-2022
Date: 2022
Publication information: Blood Advances 2022; 6(12): 3779-3791.
Abstract: Telomere biology disorders (TBDs) are a spectrum of multisystem inherited disorders characterized by bone marrow failure, resulting from mutations in genes encoding telomerase or other proteins involved in maintaining telomere length and integrity. Pathogenicity of variants in these genes can be hard to evaluate, since TBD mutations show highly variable penetrance and genetic anticipation due to inheritance of shorter telomeres with each generation. Thus, detailed functional analysis of newly identified variants is often essential. Here we describe a patient with compound heterozygous variants in the TERT gene, which encodes the catalytic subunit of telomerase, hTERT; this patient has the extremely severe Hoyeraal-Hreidarsson form of TBD, although his heterozygous parents are clinically unaffected. Molecular dynamic modeling and detailed biochemical analyses demonstrate that 1 allele (L557P) affects association of hTERT with its cognate RNA component hTR, while the other (K1050E) affects the binding of telomerase to its DNA substrate and enzyme processivity. Unexpectedly, the data demonstrate a functional interaction between the proteins encoded by the 2 alleles, with WT hTERT able to rescue the effect of K1050E on processivity, whereas L557P hTERT cannot. These data contribute to the mechanistic understanding of telomerase, indicating that RNA binding in 1 hTERT molecule affects the processivity of telomere addition by the other molecule. This work emphasizes the importance of functional characterization of TERT variants to reach a definitive molecular diagnosis for TBD patients, and in particular it illustrates the importance of analyzing the effects of compound heterozygous variants in combination to reveal interallelic effects.
DOI: 10.1182/bloodadvances.2022007029
ORCID: 0000-0001-6636-2555
Journal: Blood Advances
PubMed URL: 35477117
PubMed URL:
Type: Journal Article
Appears in Collections:Journal articles

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