Identification, clinical manifestation and structural mechanisms of mutations in AMPK associated cardiac glycogen storage disease.
Arrhythmia
Cardiomyopathy
Genetics
Heart failure
PRKAG2 syndrome
Sudden cardiac death
Journal
EBioMedicine
ISSN: 2352-3964
Titre abrégé: EBioMedicine
Pays: Netherlands
ID NLM: 101647039
Informations de publication
Date de publication:
Apr 2020
Apr 2020
Historique:
received:
11
09
2019
revised:
08
02
2020
accepted:
03
03
2020
pubmed:
8
4
2020
medline:
26
1
2021
entrez:
8
4
2020
Statut:
ppublish
Résumé
Although 21 causative mutations have been associated with PRKAG2 syndrome, our understanding of the syndrome remains incomplete. The aim of this project is to further investigate its unique genetic background, clinical manifestations, and underlying structural changes. We recruited 885 hypertrophic cardiomyopathy (HCM) probands and their families internationally. Targeted next-generation sequencing of sudden cardiac death (SCD) genes was performed. The role of the identified variants was assessed using histological techniques and computational modeling. Twelve PRKAG2 syndrome kindreds harboring 5 distinct variants were identified. The clinical penetrance of 25 carriers was 100.0%. Twenty-two family members died of SCD or heart failure (HF). All probands developed bradycardia (HRmin, 36.3 ± 9.8 bpm) and cardiac conduction defects, and 33% had evidence of atrial fibrillation/paroxysmal supraventricular tachycardia (PSVT) and 67% had ventricular preexcitation, respectively. Some carriers presented with apical hypertrophy, hypertension, hyperlipidemia, and renal insufficiency. Histological study revealed reduced AMPK activity and major cardiac channels in the heart tissue with K485E mutation. Computational modelling suggests that K485E disrupts the salt bridge connecting the β and γ subunits of AMPK, R302Q/P decreases the binding affinity for ATP, T400N and H401D alter the orientation of H383 and R531 residues, thus altering nucleotide binding, and N488I and L341S lead to structural instability in the Bateman domain, which disrupts the intramolecular regulation. Including 4 families with 3 new mutations, we describe a cohort of 12 kindreds with PRKAG2 syndrome with novel pathogenic mechanisms by computational modelling. Severe clinical cardiac phenotypes may be developed, including HF, requiring close follow-up.
Sections du résumé
BACKGROUND
BACKGROUND
Although 21 causative mutations have been associated with PRKAG2 syndrome, our understanding of the syndrome remains incomplete. The aim of this project is to further investigate its unique genetic background, clinical manifestations, and underlying structural changes.
METHODS
METHODS
We recruited 885 hypertrophic cardiomyopathy (HCM) probands and their families internationally. Targeted next-generation sequencing of sudden cardiac death (SCD) genes was performed. The role of the identified variants was assessed using histological techniques and computational modeling.
FINDINGS
RESULTS
Twelve PRKAG2 syndrome kindreds harboring 5 distinct variants were identified. The clinical penetrance of 25 carriers was 100.0%. Twenty-two family members died of SCD or heart failure (HF). All probands developed bradycardia (HRmin, 36.3 ± 9.8 bpm) and cardiac conduction defects, and 33% had evidence of atrial fibrillation/paroxysmal supraventricular tachycardia (PSVT) and 67% had ventricular preexcitation, respectively. Some carriers presented with apical hypertrophy, hypertension, hyperlipidemia, and renal insufficiency. Histological study revealed reduced AMPK activity and major cardiac channels in the heart tissue with K485E mutation. Computational modelling suggests that K485E disrupts the salt bridge connecting the β and γ subunits of AMPK, R302Q/P decreases the binding affinity for ATP, T400N and H401D alter the orientation of H383 and R531 residues, thus altering nucleotide binding, and N488I and L341S lead to structural instability in the Bateman domain, which disrupts the intramolecular regulation.
INTERPRETATION
CONCLUSIONS
Including 4 families with 3 new mutations, we describe a cohort of 12 kindreds with PRKAG2 syndrome with novel pathogenic mechanisms by computational modelling. Severe clinical cardiac phenotypes may be developed, including HF, requiring close follow-up.
Identifiants
pubmed: 32259713
pii: S2352-3964(20)30098-0
doi: 10.1016/j.ebiom.2020.102723
pmc: PMC7132172
pii:
doi:
Substances chimiques
Adenosine Triphosphate
8L70Q75FXE
PRKAG2 protein, human
EC 2.7.11.1
AMP-Activated Protein Kinases
EC 2.7.11.31
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
102723Subventions
Organisme : NHLBI NIH HHS
ID : R01 HL047678
Pays : United States
Organisme : NHLBI NIH HHS
ID : R56 HL138103
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Competing Interest The authors report no relationships that could be construed as a conflict of interest.
Références
Oncogene. 2015 Mar 19;34(12):1608
pubmed: 25790189
Circ Arrhythm Electrophysiol. 2016 Jan;9(1):e003121
pubmed: 26729852
Cell Rep. 2016 Dec 20;17(12):3292-3304
pubmed: 28009297
J Cardiovasc Magn Reson. 2015 Oct 24;17:89
pubmed: 26496977
Europace. 2020 Aug 1;22(8):1278
pubmed: 32215636
Nat Commun. 2017 Nov 2;8(1):1258
pubmed: 29097735
Proteins. 2017 Jun;85(6):1056-1064
pubmed: 28241380
Cell Metab. 2016 May 10;23(5):821-36
pubmed: 27133129
J Mol Cell Cardiol. 2018 Apr;117:49-61
pubmed: 29452156
J Biol Chem. 2016 Nov 4;291(45):23428-23439
pubmed: 27621313
Heart Rhythm. 2011 Jan;8(1):58-64
pubmed: 20888928
Eur Heart J. 2007 Dec;28(24):3076-93
pubmed: 17959624
Eur Heart J. 2002 May;23(9):679-81
pubmed: 11977988
N Engl J Med. 2001 Jun 14;344(24):1823-31
pubmed: 11407343
Pediatr Res. 2007 Oct;62(4):499-504
pubmed: 17667862
N Engl J Med. 2008 May 1;358(18):1899-908
pubmed: 18403758
PLoS One. 2013 May 31;8(5):e64603
pubmed: 23741347
Eur J Heart Fail. 2006 Nov;8(7):712-5
pubmed: 16716659
Am J Hum Genet. 2005 Jun;76(6):1034-49
pubmed: 15877279
Nat Genet. 2010 May;42(5):376-84
pubmed: 20383146
J Am Coll Cardiol. 2005 Mar 15;45(6):922-30
pubmed: 15766830
Biochim Biophys Acta. 2010 Feb;1802(2):284-91
pubmed: 20005292
Circ Arrhythm Electrophysiol. 2016 Dec;9(12):
pubmed: 27864312
Eur Heart J Case Rep. 2019 Jun 1;3(2):
pubmed: 31449595
Circulation. 2011 Dec 13;124(24):e783-831
pubmed: 22068434
J Clin Invest. 2002 Feb;109(3):357-62
pubmed: 11827995
Circulation. 2005 Jan 4;111(1):21-9
pubmed: 15611370
Cell Res. 2016 Oct;26(10):1099-1111
pubmed: 27573176
Europace. 2017 Apr 1;19(4):651-659
pubmed: 28431061
J Biol Chem. 2004 Sep 10;279(37):38441-7
pubmed: 15247217
Circulation. 2001 Dec 18;104(25):3030-3
pubmed: 11748095
Eur Heart J. 2014 Oct 14;35(39):2733-79
pubmed: 25173338
Methods Mol Biol. 2018;1732:581-619
pubmed: 29480501