Variants in ADD1 cause intellectual disability, corpus callosum dysgenesis, and ventriculomegaly in humans.
Adducin
Alternative splicing
Axon degeneration
Membrane-associated periodic ring-like structure (MPS)
Journal
Genetics in medicine : official journal of the American College of Medical Genetics
ISSN: 1530-0366
Titre abrégé: Genet Med
Pays: United States
ID NLM: 9815831
Informations de publication
Date de publication:
02 2022
02 2022
Historique:
received:
25
05
2021
revised:
24
08
2021
accepted:
21
09
2021
pubmed:
16
12
2021
medline:
23
3
2022
entrez:
15
12
2021
Statut:
ppublish
Résumé
Adducins interconnect spectrin and actin filaments to form polygonal scaffolds beneath the cell membranes and form ring-like structures in neuronal axons. Adducins regulate mouse neural development, but their function in the human brain is unknown. We used exome sequencing to uncover ADD1 variants associated with intellectual disability (ID) and brain malformations. We studied ADD1 splice isoforms in mouse and human neocortex development with RNA sequencing, super resolution imaging, and immunoblotting. We investigated 4 variant ADD1 proteins and heterozygous ADD1 cells for protein expression and ADD1-ADD2 dimerization. We studied Add1 functions in vivo using Add1 knockout mice. We uncovered loss-of-function ADD1 variants in 4 unrelated individuals affected by ID and/or structural brain defects. Three additional de novo copy number variations covering the ADD1 locus were associated with ID and brain malformations. ADD1 is highly expressed in the neocortex and the corpus callosum, whereas ADD1 splice isoforms are dynamically expressed between cortical progenitors and postmitotic neurons. Human variants impair ADD1 protein expression and/or dimerization with ADD2. Add1 knockout mice recapitulate corpus callosum dysgenesis and ventriculomegaly phenotypes. Our human and mouse genetics results indicate that pathogenic ADD1 variants cause corpus callosum dysgenesis, ventriculomegaly, and/or ID.
Identifiants
pubmed: 34906466
pii: S1098-3600(21)04742-0
doi: 10.1016/j.gim.2021.09.014
pmc: PMC8802223
mid: NIHMS1771997
pii:
doi:
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
319-331Subventions
Organisme : NINDS NIH HHS
ID : R01 NS032457
Pays : United States
Organisme : NICHD NIH HHS
ID : P50 HD105351
Pays : United States
Organisme : NICHD NIH HHS
ID : P50 HD105354
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS035129
Pays : United States
Organisme : NIMH NIH HHS
ID : K01 MH109747
Pays : United States
Organisme : NIGMS NIH HHS
ID : DP2 GM137423
Pays : United States
Organisme : Howard Hughes Medical Institute
Pays : United States
Informations de copyright
Copyright © 2021 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Conflict of Interest R.D.G receives consulting fees from Minovia Therapeutics. All other authors declare no conflicts of interest.
Références
Neuron. 2011 Mar 24;69(6):1132-46
pubmed: 21435558
Blood. 2008 Nov 15;112(10):4298-307
pubmed: 18723693
Brain. 2014 Jun;137(Pt 6):1579-613
pubmed: 24477430
Cell Rep. 2018 Jan 30;22(5):1151-1158
pubmed: 29386104
Proc Natl Acad Sci U S A. 1999 Sep 14;96(19):10717-22
pubmed: 10485892
Mol Biol Cell. 2008 Feb;19(2):536-45
pubmed: 18003973
Science. 2013 Jan 25;339(6118):452-6
pubmed: 23239625
Hypertension. 2002 Jun;39(6):1053-7
pubmed: 12052841
Nature. 2016 Dec 15;540(7633):423-427
pubmed: 27919067
Nat Genet. 2021 Jul;53(7):1006-1021
pubmed: 34211179
Neuron. 2012 Apr 26;74(2):285-99
pubmed: 22542183
Nat Rev Neurosci. 2016 May;17(5):265-81
pubmed: 27094079
Proc Natl Acad Sci U S A. 2012 Jul 17;109(29):11836-41
pubmed: 22753484
Pediatr Neurosci. 1985-1986;12(2):101-3
pubmed: 2428024
Cereb Cortex. 2013 Aug;23(8):1824-35
pubmed: 22705452
Lancet. 1997 May 10;349(9062):1353-7
pubmed: 9149697
Nature. 2011 May 26;473(7348):514-8
pubmed: 21532590
J Biol Chem. 1990 Aug 5;265(22):13130-6
pubmed: 2376589
Nat Protoc. 2006;1(5):2406-15
pubmed: 17406484
Clin Genet. 2004 Oct;66(4):276-89
pubmed: 15355427
J Biol Chem. 1998 Jul 24;273(30):19329-38
pubmed: 9668123
Nature. 2016 Aug 17;536(7616):285-91
pubmed: 27535533
Annu Rev Cell Biol. 1993;9:27-66
pubmed: 8280463
Nature. 1987 Jul 23-29;328(6128):359-62
pubmed: 3600811
Cell. 2016 Aug 25;166(5):1147-1162.e15
pubmed: 27565344
J Biol Chem. 1995 Aug 11;270(32):18990-6
pubmed: 7642559
Physiol Rev. 2001 Jul;81(3):1353-92
pubmed: 11427698
Science. 2020 Sep 11;369(6509):
pubmed: 32913072
Elife. 2014 Dec 23;3:
pubmed: 25535840
Proc Natl Acad Sci U S A. 2019 Jul 30;116(31):15686-15695
pubmed: 31209033
Mol Syndromol. 2016 Sep;7(4):220-233
pubmed: 27781032
J Cell Biol. 1987 Dec;105(6 Pt 1):2837-45
pubmed: 3693401
Cell Mol Life Sci. 2000 Jun;57(6):884-95
pubmed: 10950304
Nat Rev Neurosci. 2007 Apr;8(4):287-99
pubmed: 17375041
Nat Biotechnol. 2011 Jan;29(1):24-6
pubmed: 21221095
Eur J Med Genet. 2016 Jan;59(1):26-31
pubmed: 26723519
EMBO J. 2012 Mar 21;31(6):1453-66
pubmed: 22307086
Cell Rep. 2016 Apr 19;15(3):490-498
pubmed: 27068466
Biochem Biophys Res Commun. 2017 Dec 9;494(1-2):234-241
pubmed: 29032200