Functional interaction between compound heterozygous TERT mutations causes severe telomere biology disorder.
Journal
Blood advances
ISSN: 2473-9537
Titre abrégé: Blood Adv
Pays: United States
ID NLM: 101698425
Informations de publication
Date de publication:
28 06 2022
28 06 2022
Historique:
received:
11
01
2022
accepted:
07
04
2022
pubmed:
28
4
2022
medline:
29
6
2022
entrez:
27
4
2022
Statut:
ppublish
Résumé
Telomere biology disorders (TBDs) are a spectrum of multisystem inherited disorders characterized by bone marrow failure, resulting from mutations in the genes encoding telomerase or other proteins involved in maintaining telomere length and integrity. Pathogenicity of variants in these genes can be hard to evaluate, because TBD mutations show highly variable penetrance and genetic anticipation related to inheritance of shorter telomeres with each generation. Thus, detailed functional analysis of newly identified variants is often essential. Herein, we describe a patient with compound heterozygous variants in the TERT gene, which encodes the catalytic subunit of telomerase, hTERT. This patient had the extremely severe Hoyeraal-Hreidarsson form of TBD, although his heterozygous parents were clinically unaffected. Molecular dynamic modeling and detailed biochemical analyses demonstrate that one allele (L557P) affects association of hTERT with its cognate RNA component hTR, whereas 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 two alleles, with wild-type hTERT rescuing the effect of K1050E on processivity, whereas L557P hTERT does not. These data contribute to the mechanistic understanding of telomerase, indicating that RNA binding in one 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 patients with TBD, and, in particular, it illustrates the importance of analyzing the effects of compound heterozygous variants in combination, to reveal interallelic effects.
Identifiants
pubmed: 35477117
pii: 485094
doi: 10.1182/bloodadvances.2022007029
pmc: PMC9631560
doi:
Substances chimiques
RNA
63231-63-0
TERT protein, human
EC 2.7.7.49
Telomerase
EC 2.7.7.49
Types de publication
Case Reports
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3779-3791Informations de copyright
© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.
Références
Annu Rev Biochem. 2017 Jun 20;86:439-460
pubmed: 28141967
Biochim Biophys Acta. 2010 May;1804(5):1190-201
pubmed: 19665593
Biochimie. 2016 Sep-Oct;128-129:114-21
pubmed: 27456246
J Mol Graph. 1996 Feb;14(1):33-8, 27-8
pubmed: 8744570
Nat Genet. 1998 May;19(1):32-8
pubmed: 9590285
Genet Med. 2015 May;17(5):405-24
pubmed: 25741868
J Biol Chem. 2000 Aug 4;275(31):24199-207
pubmed: 10807925
Nature. 2021 May;593(7859):449-453
pubmed: 33883742
Nucleic Acids Res. 2013 Oct;41(19):8969-78
pubmed: 23901009
Orphanet J Rare Dis. 2020 Oct 23;15(1):299
pubmed: 33097095
Mol Cell Biol. 1991 Sep;11(9):4572-80
pubmed: 1875940
Blood. 2013 May 2;121(18):3586-93
pubmed: 23538340
Bioinformatics. 2013 Apr 1;29(7):845-54
pubmed: 23407358
Mol Cell. 2005 Mar 4;17(5):671-82
pubmed: 15749017
Nucleic Acids Res. 2009 Feb;37(3):e21
pubmed: 19129229
Nature. 2001 Sep 27;413(6854):432-5
pubmed: 11574891
Haematologica. 2020 Feb 13;106(1):64-73
pubmed: 32054657
Biochimie. 2008 Jan;90(1):122-30
pubmed: 17825470
F1000Res. 2018 May 1;7:
pubmed: 29770205
J Biol Chem. 2017 Mar 17;292(11):4593-4601
pubmed: 28154186
Blood. 1997 Jul 1;90(1):182-93
pubmed: 9207452
Proc Natl Acad Sci U S A. 2005 Nov 1;102(44):15960-4
pubmed: 16247010
Intern Med J. 2016 Apr;46(4):393-403
pubmed: 26247919
Mol Cell. 2021 Jun 3;81(11):2349-2360.e6
pubmed: 33852895
Nat Med. 1999 Oct;5(10):1164-70
pubmed: 10502820
EMBO J. 1995 Sep 1;14(17):4240-8
pubmed: 7556065
Nat Genet. 2004 May;36(5):447-9
pubmed: 15098033
Mol Cell. 2000 Aug;6(2):493-9
pubmed: 10983995
Nat Struct Mol Biol. 2013 Apr;20(4):454-60
pubmed: 23474713
Sci Adv. 2020 Apr 10;6(15):eaay3511
pubmed: 32300648
PLoS Genet. 2011 Mar;7(3):e1001352
pubmed: 21483807
Mol Cell Biol. 2001 Sep;21(18):6151-60
pubmed: 11509658
Proc Natl Acad Sci U S A. 2007 May 1;104(18):7552-7
pubmed: 17460043
Eur Respir J. 2021 Feb 11;57(2):
pubmed: 33214205
Science. 2007 Mar 30;315(5820):1850-3
pubmed: 17395830
EMBO J. 2012 Jan 4;31(1):150-61
pubmed: 21989387
Am J Respir Crit Care Med. 2008 Oct 1;178(7):729-37
pubmed: 18635888
Cell. 2018 May 17;173(5):1179-1190.e13
pubmed: 29775593
Acta Paediatr Scand. 1988 Sep;77(5):773-5
pubmed: 3201986
EMBO J. 2010 Mar 3;29(5):924-33
pubmed: 20094033
Structure. 2007 Nov;15(11):1403-12
pubmed: 17997966
Biochem J. 2015 Jan 15;465(2):347-57
pubmed: 25365545
Nature. 1999 Dec 2;402(6761):551-5
pubmed: 10591218
Blood. 2008 Feb 1;111(3):1128-30
pubmed: 18042801
Annu Rev Biophys. 2017 May 22;46:357-377
pubmed: 28375735
J Clin Invest. 2013 Mar;123(3):996-1002
pubmed: 23454763
N Engl J Med. 2005 Apr 7;352(14):1413-24
pubmed: 15814878
Cell. 1989 Nov 3;59(3):521-9
pubmed: 2805070
Methods. 2017 Feb 1;114:85-95
pubmed: 27507660
Nucleic Acids Res. 2010 Apr;38(6):1982-96
pubmed: 20044353
Genes Dev. 1999 Sep 15;13(18):2388-99
pubmed: 10500096
Blood. 2005 Jan 15;105(2):682-8
pubmed: 15238429
Blood. 2009 Jan 8;113(2):309-16
pubmed: 18931339
Hum Mol Genet. 2017 May 15;26(10):1900-1914
pubmed: 28369633
Mol Cell Biol. 2001 Feb;21(4):990-1000
pubmed: 11158287
EMBO J. 2001 Jul 2;20(13):3526-34
pubmed: 11432839
Mol Biol Cell. 2003 Jan;14(1):1-13
pubmed: 12529422
Acta Paediatr Scand. 1970 Mar;59(2):185-91
pubmed: 5442429
Cell. 2012 Aug 3;150(3):481-94
pubmed: 22863003
Blood. 2007 Jan 15;109(2):524-32
pubmed: 16990594
Nucleic Acids Res. 2008 Jan;36(Database issue):D339-43
pubmed: 18073191
J Med Genet. 1992 Sep;29(9):673-5
pubmed: 1404302
Blood Cells Mol Dis. 2005 May-Jun;34(3):257-63
pubmed: 15885610
Genet Med. 2010 Dec;12(12):753-64
pubmed: 21189492
RNA Biol. 2016 Aug 2;13(8):696-706
pubmed: 26400640
Neoplasia. 2000 Sep-Oct;2(5):426-32
pubmed: 11191109
Sci Adv. 2019 Oct 02;5(10):eaav4409
pubmed: 31616780
Curr Protoc Bioinformatics. 2020 Dec;72(1):e108
pubmed: 33315308
J Natl Cancer Inst. 2013 Apr 3;105(7):459-68
pubmed: 23468462
Science. 1997 Aug 15;277(5328):955-9
pubmed: 9252327
Structure. 2013 Oct 8;21(10):1870-8
pubmed: 24055314
Mutat Res. 2012 Feb 1;730(1-2):59-67
pubmed: 21663926
Br J Cancer. 2007 Apr 10;96(7):1020-4
pubmed: 17353922
EMBO J. 2017 Jul 3;36(13):1908-1927
pubmed: 28495680
Proteins. 2010 Jun;78(8):1950-8
pubmed: 20408171
Proteins. 1995 Nov;23(3):318-26
pubmed: 8710825
Mol Cell Biol. 2002 Feb;22(4):1253-65
pubmed: 11809815