DAAM2 Variants Cause Nephrotic Syndrome via Actin Dysregulation.
Actins
/ metabolism
Alleles
Animals
Animals, Genetically Modified
Cell Movement
/ genetics
Cytoplasm
/ metabolism
Formins
/ metabolism
Genetic Variation
Humans
Kidney
/ metabolism
Kidney Glomerulus
/ metabolism
Microfilament Proteins
/ genetics
Mutation, Missense
Nephrotic Syndrome
/ genetics
Podocytes
/ metabolism
Pseudopodia
/ metabolism
RNA, Small Interfering
/ metabolism
Exome Sequencing
Xenopus
rho GTP-Binding Proteins
/ genetics
DAAM2
actin cytoskeleton
formins
monogenic kidney diseases
podocytopathy
steroid-resistant nephrotic syndrome
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:
03 12 2020
03 12 2020
Historique:
received:
15
09
2020
accepted:
05
11
2020
pubmed:
25
11
2020
medline:
13
1
2021
entrez:
24
11
2020
Statut:
ppublish
Résumé
The discovery of >60 monogenic causes of nephrotic syndrome (NS) has revealed a central role for the actin regulators RhoA/Rac1/Cdc42 and their effectors, including the formin INF2. By whole-exome sequencing (WES), we here discovered bi-allelic variants in the formin DAAM2 in four unrelated families with steroid-resistant NS. We show that DAAM2 localizes to the cytoplasm in podocytes and in kidney sections. Further, the variants impair DAAM2-dependent actin remodeling processes: wild-type DAAM2 cDNA, but not cDNA representing missense variants found in individuals with NS, rescued reduced podocyte migration rate (PMR) and restored reduced filopodia formation in shRNA-induced DAAM2-knockdown podocytes. Filopodia restoration was also induced by the formin-activating molecule IMM-01. DAAM2 also co-localizes and co-immunoprecipitates with INF2, which is intriguing since variants in both formins cause NS. Using in vitro bulk and TIRF microscopy assays, we find that DAAM2 variants alter actin assembly activities of the formin. In a Xenopus daam2-CRISPR knockout model, we demonstrate actin dysregulation in vivo and glomerular maldevelopment that is rescued by WT-DAAM2 mRNA. We conclude that DAAM2 variants are a likely cause of monogenic human SRNS due to actin dysregulation in podocytes. Further, we provide evidence that DAAM2-associated SRNS may be amenable to treatment using actin regulating compounds.
Identifiants
pubmed: 33232676
pii: S0002-9297(20)30405-5
doi: 10.1016/j.ajhg.2020.11.008
pmc: PMC7820625
pii:
doi:
Substances chimiques
Actins
0
DAAM2 protein, human
0
Formins
0
Microfilament Proteins
0
RNA, Small Interfering
0
rho GTP-Binding Proteins
EC 3.6.5.2
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
1113-1128Subventions
Organisme : NIDDK NIH HHS
ID : RC2 DK122397
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM083137
Pays : United States
Organisme : NICHD NIH HHS
ID : K12 HD052896
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR001863
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK079310
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM134895
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK076683
Pays : United States
Organisme : NICHD NIH HHS
ID : R01 HD081379
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM007205
Pays : United States
Organisme : NICHD NIH HHS
ID : R01 HD102186
Pays : United States
Organisme : NHGRI NIH HHS
ID : U24 HG008956
Pays : United States
Organisme : NHGRI NIH HHS
ID : UM1 HG006504
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM007223
Pays : United States
Organisme : NIDDK NIH HHS
ID : T32 DK007726
Pays : United States
Organisme : NIDDK NIH HHS
ID : F32 DK122766
Pays : United States
Informations de copyright
Copyright © 2020 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
Références
J Cell Sci. 2013 Jan 1;126(Pt 1):1-7
pubmed: 23516326
Nat Med. 2018 Nov;24(11):1721-1731
pubmed: 30275566
Dev Cell. 2018 Dec 17;47(6):741-757.e8
pubmed: 30503751
Nat Genet. 2000 Mar;24(3):251-6
pubmed: 10700177
N Engl J Med. 2011 Dec 22;365(25):2377-88
pubmed: 22187985
Blood. 1985 Feb;65(2):397-406
pubmed: 2981587
Clin J Am Soc Nephrol. 2014 Jun 6;9(6):1109-16
pubmed: 24742477
Curr Biol. 2013 Jul 22;23(14):1373-9
pubmed: 23850281
Nat Cell Biol. 2002 Aug;4(8):626-31
pubmed: 12134165
J Clin Invest. 2014 Mar;124(3):1098-113
pubmed: 24531545
Cytoskeleton (Hoboken). 2012 Jun;69(6):393-405
pubmed: 22605659
Nat Rev Nephrol. 2016 Mar;12(3):133-46
pubmed: 26750453
J Am Soc Nephrol. 2018 Feb;29(2):416-422
pubmed: 29114040
Dev Dyn. 2011 Jun;240(6):1558-66
pubmed: 21465621
J Biol Chem. 1971 Aug 10;246(15):4866-71
pubmed: 4254541
Proc Natl Acad Sci U S A. 2020 Jan 7;117(1):439-447
pubmed: 31871199
J Biol Chem. 1980 Feb 25;255(4):1670-6
pubmed: 6892570
Biochem Soc Trans. 2005 Dec;33(Pt 6):1256-9
pubmed: 16246092
Dev Dyn. 2002 Dec;225(4):499-510
pubmed: 12454926
Nat Genet. 2010 Jan;42(1):72-6
pubmed: 20023659
Cell. 2006 Jan 27;124(2):423-35
pubmed: 16439214
Neuron. 2015 Mar 18;85(6):1227-43
pubmed: 25754822
J Biol Chem. 2006 Feb 17;281(7):4300-7
pubmed: 16361707
J Clin Invest. 2013 Aug;123(8):3243-53
pubmed: 23867502
J Clin Invest. 2012 Dec;122(12):4401-11
pubmed: 23187129
Bioarchitecture. 2011 Nov 1;1(6):271-276
pubmed: 22545179
Kidney Int. 2012 Jun;81(11):1075-85
pubmed: 22278020
Mol Biol Cell. 2004 Feb;15(2):896-907
pubmed: 14657240
J Biol Chem. 2014 Oct 31;289(44):30602-13
pubmed: 25246531
Nephrol Dial Transplant. 2016 Nov;31(11):1802-1813
pubmed: 26507970
J Clin Invest. 2017 Dec 1;127(12):4257-4269
pubmed: 29058690
J Clin Invest. 2015 Jun;125(6):2375-84
pubmed: 25961457
Clin J Am Soc Nephrol. 2018 Jan 6;13(1):53-62
pubmed: 29127259
Dev Cell. 2012 Jan 17;22(1):183-96
pubmed: 22227309
Nat Methods. 2012 Jun 28;9(7):676-82
pubmed: 22743772
Curr Protoc Cell Biol. 2017 Dec 11;77:12.13.1-12.13.24
pubmed: 29227552
Trends Biochem Sci. 2005 Jun;30(6):342-53
pubmed: 15950879
Kidney Int. 2013 Nov;84(5):920-30
pubmed: 23677246
J Biol Chem. 2008 Mar 28;283(13):8746-55
pubmed: 18218625
J Am Soc Nephrol. 2018 Aug;29(8):2060-2068
pubmed: 29794128
Dev Biol. 2015 Dec 15;408(2):196-204
pubmed: 26546975
Kidney Int. 2019 Sep;96(3):642-655
pubmed: 31171376
Nat Genet. 2016 Apr;48(4):457-65
pubmed: 26878725
J Am Soc Nephrol. 2015 Jun;26(6):1279-89
pubmed: 25349199
Science. 2018 May 18;360(6390):758-763
pubmed: 29622724
Nature. 2019 Apr;568(7751):193-197
pubmed: 30944477
Hum Mutat. 2011 Mar;32(3):345-53
pubmed: 21309031
Curr Biol. 2017 Jul 10;27(13):1990-1998.e5
pubmed: 28625780
Curr Biol. 2003 Aug 5;13(15):1335-40
pubmed: 12906795
N Engl J Med. 2011 Jul 28;365(4):295-306
pubmed: 21756023
Dev Cell. 2006 Jun;10(6):693-706
pubmed: 16740473
Dev Biol. 2015 Dec 1;408(1):126-39
pubmed: 26526197
Curr Biol. 2002 Dec 10;12(23):R796
pubmed: 12477401
Pediatr Nephrol. 2018 Feb;33(2):305-314
pubmed: 28921387
Science. 2002 Jul 26;297(5581):612-5
pubmed: 12052901
J Am Soc Nephrol. 2011 Sep;22(9):1621-30
pubmed: 21804090
J Biol Chem. 2001 Jan 26;276(4):2824-30
pubmed: 11035012
J Biol Chem. 2010 Jul 16;285(29):22676-88
pubmed: 20472933
Methods Mol Biol. 2012;917:33-41
pubmed: 22956081
Nat Rev Mol Cell Biol. 2010 Jan;11(1):62-74
pubmed: 19997130
Am J Kidney Dis. 2020 Oct;76(4):460-470
pubmed: 32359821
PLoS One. 2014 Sep 03;9(9):e106621
pubmed: 25184792
EBioMedicine. 2014 Nov 13;1(2-3):107-15
pubmed: 26086034
FASEB J. 2019 Dec;33(12):14450-14460
pubmed: 31675484
J Am Soc Nephrol. 2012 Jul;23(7):1149-54
pubmed: 22518006
Cancer Res. 2013 Nov 15;73(22):6793-803
pubmed: 24242070
Nat Commun. 2018 May 17;9(1):1960
pubmed: 29773874
JCI Insight. 2017 Aug 17;2(16):
pubmed: 28814668
J Am Soc Nephrol. 2020 Feb;31(2):374-391
pubmed: 31924668
Annu Rev Biochem. 2007;76:593-627
pubmed: 17373907
Curr Biol. 2011 Mar 8;21(5):384-90
pubmed: 21333540
Proc Natl Acad Sci U S A. 2011 Feb 15;108(7):2933-8
pubmed: 21278336
Nat Rev Nephrol. 2016 Nov;12(11):692-710
pubmed: 27573725
Clin J Am Soc Nephrol. 2020 Jan 7;15(1):89-100
pubmed: 31831576
Mol Biol Cell. 2016 Jan 1;27(1):1-6
pubmed: 26715420
Nephron Exp Nephrol. 2010;114(3):e93-e106
pubmed: 19955829
Dev Cell. 2013 Sep 30;26(6):629-44
pubmed: 24091014