Mutation-specific pathophysiological mechanisms define different neurodevelopmental disorders associated with SATB1 dysfunction.
HPO-based analysis
SATB1
cell-based functional assays
de novo variants
intellectual disability
neurodevelopmental disorders
seizures
teeth abnormalities
Journal
American journal of human genetics
ISSN: 1537-6605
Titre abrégé: Am J Hum Genet
Pays: United States
ID NLM: 0370475
Informations de publication
Date de publication:
04 02 2021
04 02 2021
Historique:
received:
19
10
2020
accepted:
10
01
2021
pubmed:
30
1
2021
medline:
20
2
2021
entrez:
29
1
2021
Statut:
ppublish
Résumé
Whereas large-scale statistical analyses can robustly identify disease-gene relationships, they do not accurately capture genotype-phenotype correlations or disease mechanisms. We use multiple lines of independent evidence to show that different variant types in a single gene, SATB1, cause clinically overlapping but distinct neurodevelopmental disorders. Clinical evaluation of 42 individuals carrying SATB1 variants identified overt genotype-phenotype relationships, associated with different pathophysiological mechanisms, established by functional assays. Missense variants in the CUT1 and CUT2 DNA-binding domains result in stronger chromatin binding, increased transcriptional repression, and a severe phenotype. In contrast, variants predicted to result in haploinsufficiency are associated with a milder clinical presentation. A similarly mild phenotype is observed for individuals with premature protein truncating variants that escape nonsense-mediated decay, which are transcriptionally active but mislocalized in the cell. Our results suggest that in-depth mutation-specific genotype-phenotype studies are essential to capture full disease complexity and to explain phenotypic variability.
Identifiants
pubmed: 33513338
pii: S0002-9297(21)00007-0
doi: 10.1016/j.ajhg.2021.01.007
pmc: PMC7895900
pii:
doi:
Substances chimiques
Chromatin
0
Matrix Attachment Region Binding Proteins
0
SATB1 protein, human
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
346-356Subventions
Organisme : Medical Research Council
ID : MR/M014568/1
Pays : United Kingdom
Informations de copyright
Copyright © 2021 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
Références
Genes Dev. 2000 Mar 1;14(5):521-35
pubmed: 10716941
Nucleic Acids Res. 2012 May;40(9):4193-202
pubmed: 22241778
Clin Genet. 2016 Jun;89(6):728-32
pubmed: 26596517
Nat Immunol. 2017 Feb;18(2):173-183
pubmed: 27992401
Mol Cell Biol. 2005 Mar;25(5):1620-33
pubmed: 15713622
J Biol Chem. 1997 Apr 25;272(17):11463-70
pubmed: 9111059
Hum Mutat. 2015 Oct;36(10):928-30
pubmed: 26220891
Am J Hum Genet. 2019 Jun 6;104(6):1210-1222
pubmed: 31079897
J Gen Intern Med. 2014 Aug;29 Suppl 3:S780-7
pubmed: 25029978
Am J Hum Genet. 2009 Apr;84(4):524-33
pubmed: 19344873
Hum Mutat. 2019 Aug;40(8):1013-1029
pubmed: 31021519
Nat Genet. 2019 Nov;51(11):1645-1651
pubmed: 31659324
Am J Hum Genet. 2017 Sep 7;101(3):466-477
pubmed: 28886345
Am J Hum Genet. 2019 Jan 3;104(1):139-156
pubmed: 30595372
Nature. 2015 Oct 1;526(7571):82-90
pubmed: 26367797
Nature. 2020 May;581(7809):434-443
pubmed: 32461654
Am J Hum Genet. 2018 Jun 7;102(6):1195-1203
pubmed: 29861108
Mol Cell. 2006 Apr 21;22(2):231-43
pubmed: 16630892
Am J Hum Genet. 2005 Jun;76(6):1074-80
pubmed: 15877281
Nucleic Acids Res. 2019 Jan 8;47(D1):D1018-D1027
pubmed: 30476213
Nat Commun. 2019 Jul 19;10(1):3221
pubmed: 31324780
Nature. 2020 Oct;586(7831):757-762
pubmed: 33057194
Nat Genet. 2006 Nov;38(11):1278-88
pubmed: 17057718
Mol Cell Biol. 1986 Sep;6(9):3042-9
pubmed: 3491296
Nat Neurosci. 2016 Sep;19(9):1194-6
pubmed: 27479843
Cell. 2020 Feb 6;180(3):568-584.e23
pubmed: 31981491
Am J Hum Genet. 2017 Sep 7;101(3):478-484
pubmed: 28867141
J Biol Chem. 2008 Jun 27;283(26):18124-34
pubmed: 18408014
Am J Hum Genet. 2019 Aug 1;105(2):283-301
pubmed: 31353023