Gain and loss of TASK3 channel function and its regulation by novel variation cause KCNK9 imprinting syndrome.
Computational protein modeling
Electrophysiology
KCNK9 imprinting syndrome
Neurodevelopmental disorder
TASK3 channel
Journal
Genome medicine
ISSN: 1756-994X
Titre abrégé: Genome Med
Pays: England
ID NLM: 101475844
Informations de publication
Date de publication:
13 06 2022
13 06 2022
Historique:
received:
23
11
2021
accepted:
19
05
2022
entrez:
13
6
2022
pubmed:
14
6
2022
medline:
16
6
2022
Statut:
epublish
Résumé
Genomics enables individualized diagnosis and treatment, but large challenges remain to functionally interpret rare variants. To date, only one causative variant has been described for KCNK9 imprinting syndrome (KIS). The genotypic and phenotypic spectrum of KIS has yet to be described and the precise mechanism of disease fully understood. This study discovers mechanisms underlying KCNK9 imprinting syndrome (KIS) by describing 15 novel KCNK9 alterations from 47 KIS-affected individuals. We use clinical genetics and computer-assisted facial phenotyping to describe the phenotypic spectrum of KIS. We then interrogate the functional effects of the variants in the encoded TASK3 channel using sequence-based analysis, 3D molecular mechanic and dynamic protein modeling, and in vitro electrophysiological and functional methodologies. We describe the broader genetic and phenotypic variability for KIS in a cohort of individuals identifying an additional mutational hotspot at p.Arg131 and demonstrating the common features of this neurodevelopmental disorder to include motor and speech delay, intellectual disability, early feeding difficulties, muscular hypotonia, behavioral abnormalities, and dysmorphic features. The computational protein modeling and in vitro electrophysiological studies discover variability of the impact of KCNK9 variants on TASK3 channel function identifying variants causing gain and others causing loss of conductance. The most consistent functional impact of KCNK9 genetic variants, however, was altered channel regulation. This study extends our understanding of KIS mechanisms demonstrating its complex etiology including gain and loss of channel function and consistent loss of channel regulation. These data are rapidly applicable to diagnostic strategies, as KIS is not identifiable from clinical features alone and thus should be molecularly diagnosed. Furthermore, our data suggests unique therapeutic strategies may be needed to address the specific functional consequences of KCNK9 variation on channel function and regulation.
Sections du résumé
BACKGROUND
Genomics enables individualized diagnosis and treatment, but large challenges remain to functionally interpret rare variants. To date, only one causative variant has been described for KCNK9 imprinting syndrome (KIS). The genotypic and phenotypic spectrum of KIS has yet to be described and the precise mechanism of disease fully understood.
METHODS
This study discovers mechanisms underlying KCNK9 imprinting syndrome (KIS) by describing 15 novel KCNK9 alterations from 47 KIS-affected individuals. We use clinical genetics and computer-assisted facial phenotyping to describe the phenotypic spectrum of KIS. We then interrogate the functional effects of the variants in the encoded TASK3 channel using sequence-based analysis, 3D molecular mechanic and dynamic protein modeling, and in vitro electrophysiological and functional methodologies.
RESULTS
We describe the broader genetic and phenotypic variability for KIS in a cohort of individuals identifying an additional mutational hotspot at p.Arg131 and demonstrating the common features of this neurodevelopmental disorder to include motor and speech delay, intellectual disability, early feeding difficulties, muscular hypotonia, behavioral abnormalities, and dysmorphic features. The computational protein modeling and in vitro electrophysiological studies discover variability of the impact of KCNK9 variants on TASK3 channel function identifying variants causing gain and others causing loss of conductance. The most consistent functional impact of KCNK9 genetic variants, however, was altered channel regulation.
CONCLUSIONS
This study extends our understanding of KIS mechanisms demonstrating its complex etiology including gain and loss of channel function and consistent loss of channel regulation. These data are rapidly applicable to diagnostic strategies, as KIS is not identifiable from clinical features alone and thus should be molecularly diagnosed. Furthermore, our data suggests unique therapeutic strategies may be needed to address the specific functional consequences of KCNK9 variation on channel function and regulation.
Identifiants
pubmed: 35698242
doi: 10.1186/s13073-022-01064-4
pii: 10.1186/s13073-022-01064-4
pmc: PMC9195326
doi:
Substances chimiques
KCNK9 protein, human
0
Potassium Channels, Tandem Pore Domain
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
62Informations de copyright
© 2022. The Author(s).
Références
PLoS One. 2011 Jan 28;6(1):e15827
pubmed: 21297978
Genet Med. 2015 May;17(5):405-24
pubmed: 25741868
Biophys J. 2009 Jul 8;97(1):50-8
pubmed: 19580743
Nucleic Acids Res. 2009 Jul;37(Web Server issue):W510-4
pubmed: 19429685
Nat Methods. 2010 Apr;7(4):248-9
pubmed: 20354512
Hum Mutat. 2015 Oct;36(10):928-30
pubmed: 26220891
Nat Genet. 2019 Jan;51(1):88-95
pubmed: 30531870
Bioinformatics. 2000 Jun;16(6):566-7
pubmed: 10980157
Nat Med. 2019 Jan;25(1):60-64
pubmed: 30617323
Mol Syst Biol. 2011 Oct 11;7:539
pubmed: 21988835
J Mol Graph. 1996 Feb;14(1):33-8, 27-8
pubmed: 8744570
Nucleic Acids Res. 2003 Jul 1;31(13):3316-9
pubmed: 12824316
Physiol Rev. 2010 Apr;90(2):559-605
pubmed: 20393194
Nucleic Acids Res. 2005 Jul 1;33(Web Server issue):W382-8
pubmed: 15980494
Nature. 2020 May;581(7809):434-443
pubmed: 32461654
BMC Biol. 2012 Oct 02;10:82
pubmed: 23031578
Science. 2012 Jan 27;335(6067):436-41
pubmed: 22282805
Genet Med. 2019 Jul;21(7):1611-1620
pubmed: 30504930
Am J Hum Genet. 2008 Aug;83(2):193-9
pubmed: 18678320
Nucleic Acids Res. 2000 Jan 1;28(1):235-42
pubmed: 10592235
Nucleic Acids Res. 2016 Jul 8;44(W1):W356-60
pubmed: 27131359
BMC Bioinformatics. 2008 Jan 23;9:40
pubmed: 18215316
Neuroscientist. 2018 Aug;24(4):368-380
pubmed: 29542386
Bioinformatics. 2011 Jun 15;27(12):1711-2
pubmed: 21505037
Genome Med. 2020 Dec 2;12(1):103
pubmed: 33261662
J Comput Chem. 2005 Dec;26(16):1781-802
pubmed: 16222654
Bioinformatics. 2006 Nov 1;22(21):2695-6
pubmed: 16940322
J Physiol. 2009 Oct 15;587(Pt 20):4769-83
pubmed: 19703964
Genome Res. 2007 Dec;17(12):1723-30
pubmed: 18055845
Cereb Cortex. 2014 Apr;24(4):1017-29
pubmed: 23236211
Science. 2012 Jan 27;335(6067):432-6
pubmed: 22282804
J Neurosci. 2001 Oct 1;21(19):7491-505
pubmed: 11567039
Nat Genet. 2018 Aug;50(8):1161-1170
pubmed: 30038395
J Comput Chem. 2008 Aug;29(11):1859-65
pubmed: 18351591
Brain Res. 2011 Oct 6;1416:69-79
pubmed: 21885038
Protein Sci. 2018 Jan;27(1):112-128
pubmed: 28836357
Eur J Med Genet. 2020 Jan;63(1):103619
pubmed: 30690205
J Pharmacol Exp Ther. 2007 Dec;323(3):924-34
pubmed: 17875609
Proc Natl Acad Sci U S A. 2001 Aug 28;98(18):10037-41
pubmed: 11517324
Bioinformatics. 2021 Jun 16;37(10):1367-1375
pubmed: 33226070
J Biol Chem. 2000 Mar 31;275(13):9340-7
pubmed: 10734076
Nat Commun. 2020 Jan 24;11(1):480
pubmed: 31980599
Proc Natl Acad Sci U S A. 2009 Oct 13;106(41):17546-51
pubmed: 19805135
Nucleic Acids Res. 2019 Jan 8;47(D1):D886-D894
pubmed: 30371827
J Biomol NMR. 1996 Dec;8(4):477-86
pubmed: 9008363
J Biol Chem. 2000 Jun 2;275(22):16650-7
pubmed: 10747866
Mol Pharmacol. 2014 Mar;85(3):397-407
pubmed: 24342771
Genet Med. 2021 Mar;23(3):498-507
pubmed: 33144682
Genome Res. 2001 May;11(5):863-74
pubmed: 11337480
Nat Methods. 2014 Apr;11(4):361-2
pubmed: 24681721
J Physiol. 2007 Jan 15;578(Pt 2):377-85
pubmed: 17068099
Nature. 2020 Jun;582(7812):443-447
pubmed: 32499642
Proc Natl Acad Sci U S A. 2006 Feb 28;103(9):3422-7
pubmed: 16492788
Annu Rev Pharmacol Toxicol. 2021 Jan 6;61:401-420
pubmed: 32679007
Am J Med Genet A. 2016 Oct;170(10):2632-7
pubmed: 27151206
Biophys J. 2007 Mar 1;92(5):1503-11
pubmed: 17158570
Nucleic Acids Res. 2013 Jul;41(Web Server issue):W597-600
pubmed: 23671338
Pharmacol Rev. 2005 Dec;57(4):527-40
pubmed: 16382106
Bioinformatics. 2014 Sep 1;30(17):i505-11
pubmed: 25161240
J Physiol. 2019 Feb;597(4):1087-1101
pubmed: 30365877
Curr Opin Genet Dev. 2020 Dec;65:69-75
pubmed: 32599522
Science. 1998 Apr 3;280(5360):69-77
pubmed: 9525859
Mol Pharmacol. 2007 Jun;71(6):1666-75
pubmed: 17374744