Elongin C (ELOC/TCEB1)-associated von Hippel-Lindau disease.
Journal
Human molecular genetics
ISSN: 1460-2083
Titre abrégé: Hum Mol Genet
Pays: England
ID NLM: 9208958
Informations de publication
Date de publication:
23 08 2022
23 08 2022
Historique:
received:
10
02
2022
revised:
15
03
2022
accepted:
16
03
2022
pubmed:
25
3
2022
medline:
27
8
2022
entrez:
24
3
2022
Statut:
ppublish
Résumé
Around 95% of patients with clinical features that meet the diagnostic criteria for von Hippel-Lindau disease (VHL) have a detectable inactivating germline variant in VHL. The VHL protein (pVHL) functions as part of the E3 ubiquitin ligase complex comprising pVHL, elongin C, elongin B, cullin 2 and ring box 1 (VCB-CR complex), which plays a key role in oxygen sensing and degradation of hypoxia-inducible factors. To date, only variants in VHL have been shown to cause VHL disease. We undertook trio analysis by whole-exome sequencing in a proband with VHL disease but without a detectable VHL mutation. Molecular studies were also performed on paired DNA extracted from the proband's kidney tumour and blood and bioinformatics analysis of sporadic renal cell carcinoma (RCC) dataset was undertaken. A de novo pathogenic variant in ELOC NM_005648.4(ELOC):c.236A>G (p.Tyr79Cys) gene was identified in the proband. ELOC encodes elongin C, a key component [C] of the VCB-CR complex. The p.Tyr79Cys substitution is a mutational hotspot in sporadic VHL-competent RCC and has previously been shown to mimic the effects of pVHL deficiency on hypoxic signalling. Analysis of an RCC from the proband showed similar findings to that in somatically ELOC-mutated RCC (expression of hypoxia-responsive proteins, no somatic VHL variants and chromosome 8 loss). These findings are consistent with pathogenic ELOC variants being a novel cause for VHL disease and suggest that genetic testing for ELOC variants should be performed in individuals with suspected VHL disease with no detectable VHL variant.
Identifiants
pubmed: 35323939
pii: 6551617
doi: 10.1093/hmg/ddac066
pmc: PMC9402235
doi:
Substances chimiques
Elongin
0
Transcription Factors
0
Ubiquitin-Protein Ligases
EC 2.3.2.27
Von Hippel-Lindau Tumor Suppressor Protein
EC 2.3.2.27
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2728-2737Subventions
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/T028068/1
Pays : United Kingdom
Informations de copyright
© The Author(s) 2022. Published by Oxford University Press.
Références
Eur J Hum Genet. 2011 Jun;19(6):617-23
pubmed: 21386872
Science. 1993 May 28;260(5112):1317-20
pubmed: 8493574
Structure. 2015 Mar 3;23(3):441-449
pubmed: 25661653
Proc Natl Acad Sci U S A. 2006 May 16;103(20):7637-42
pubmed: 16675548
Nat Genet. 2011 May;43(5):491-8
pubmed: 21478889
Hum Mol Genet. 2002 Jun 15;11(13):1549-60
pubmed: 12045208
Ther Adv Urol. 2017 Oct 31;10(1):3-10
pubmed: 29344091
Curr Protoc Bioinformatics. 2013;43:11.10.1-11.10.33
pubmed: 25431634
Mod Pathol. 2015 Jun;28(6):845-853
pubmed: 25676555
Sci Rep. 2016 Aug 11;6:31128
pubmed: 27511743
J Biol Chem. 2000 May 12;275(19):14005-8
pubmed: 10747851
Bioinformatics. 2012 Sep 15;28(18):i333-i339
pubmed: 22962449
Bioinformatics. 2009 Jul 15;25(14):1754-60
pubmed: 19451168
Nature. 1999 May 20;399(6733):271-5
pubmed: 10353251
J Med Genet. 1991 Jul;28(7):443-7
pubmed: 1895313
Nature. 2016 Nov 3;539(7627):112-117
pubmed: 27595394
Genome Biol. 2016 Jun 06;17(1):122
pubmed: 27268795
Genome Res. 2010 Sep;20(9):1297-303
pubmed: 20644199
Nature. 1988 Mar 17;332(6161):268-9
pubmed: 2894613
Eur J Hum Genet. 2014 Sep;22(9):1149-52
pubmed: 24301059
Q J Med. 1990 Nov;77(283):1151-63
pubmed: 2274658
Cancer. 2012 Dec 1;118(23):5777-82
pubmed: 22605478
PLoS One. 2016 Aug 04;11(8):e0160519
pubmed: 27490490
Proc Natl Acad Sci U S A. 1996 Oct 1;93(20):10595-9
pubmed: 8855223
Science. 2001 Apr 20;292(5516):464-8
pubmed: 11292862
Hum Mol Genet. 1997 Jul;6(7):1051-6
pubmed: 9215674
Nucleic Acids Res. 2010 Sep;38(16):e164
pubmed: 20601685
J Biol Chem. 2001 Apr 20;276(16):12530-8
pubmed: 11278610
Cell Rep. 2018 Apr 3;23(1):313-326.e5
pubmed: 29617669
Nat Genet. 2013 Aug;45(8):860-7
pubmed: 23797736
Cancer Res. 2002 Jun 1;62(11):3014-9
pubmed: 12036906
Nat Cell Biol. 2001 Dec;3(12):1114-9
pubmed: 11781573
Blood. 2018 Aug 2;132(5):469-483
pubmed: 29891534
Bioinformatics. 2011 Aug 1;27(15):2156-8
pubmed: 21653522
Am J Hum Genet. 1997 Apr;60(4):765-71
pubmed: 9106522
Nature. 2013 Jul 4;499(7456):43-9
pubmed: 23792563
Genome Res. 2002 Jun;12(6):996-1006
pubmed: 12045153
J Biol Chem. 2002 Nov 1;277(44):42394-8
pubmed: 12228220
Hum Mol Genet. 1994 Dec;3(12):2169-73
pubmed: 7881415
Am J Med. 1964 Apr;36:595-617
pubmed: 14142412
Nat Genet. 1994 May;7(1):85-90
pubmed: 7915601
Bioinformatics. 2009 Aug 15;25(16):2078-9
pubmed: 19505943
Cancer Res. 2009 Jun 1;69(11):4674-81
pubmed: 19470766
Bioinformatics. 2010 Mar 15;26(6):841-2
pubmed: 20110278
Am J Hum Genet. 2003 Aug;73(2):412-9
pubmed: 12844285
Nat Rev Cancer. 2015 Jan;15(1):55-64
pubmed: 25533676
Cell. 2012 May 25;149(5):994-1007
pubmed: 22608083
Science. 1999 Apr 16;284(5413):455-61
pubmed: 10205047
Eur Urol Focus. 2021 Mar;7(2):381-389
pubmed: 31813809
J Biol Chem. 2003 Aug 22;278(34):31972-9
pubmed: 12783885