Heterozygous variants in the DVL2 interaction region of DACT1 cause CAKUT and features of Townes-Brocks syndrome 2.
Journal
Human genetics
ISSN: 1432-1203
Titre abrégé: Hum Genet
Pays: Germany
ID NLM: 7613873
Informations de publication
Date de publication:
Jan 2023
Jan 2023
Historique:
received:
08
07
2022
accepted:
16
08
2022
pubmed:
7
9
2022
medline:
18
1
2023
entrez:
6
9
2022
Statut:
ppublish
Résumé
Most patients with congenital anomalies of the kidney and urinary tract (CAKUT) remain genetically unexplained. In search of novel genes associated with CAKUT in humans, we applied whole-exome sequencing in a patient with kidney, anorectal, spinal, and brain anomalies, and identified a rare heterozygous missense variant in the DACT1 (dishevelled binding antagonist of beta catenin 1) gene encoding a cytoplasmic WNT signaling mediator. Our patient's features overlapped Townes-Brocks syndrome 2 (TBS2) previously described in a family carrying a DACT1 nonsense variant as well as those of Dact1-deficient mice. Therefore, we assessed the role of DACT1 in CAKUT pathogenesis. Taken together, very rare (minor allele frequency ≤ 0.0005) non-silent DACT1 variants were detected in eight of 209 (3.8%) CAKUT families, significantly more frequently than in controls (1.7%). All seven different DACT1 missense variants, predominantly likely pathogenic and exclusively maternally inherited, were located in the interaction region with DVL2 (dishevelled segment polarity protein 2), and biochemical characterization revealed reduced binding of mutant DACT1 to DVL2. Patients carrying DACT1 variants presented with kidney agenesis, duplex or (multi)cystic (hypo)dysplastic kidneys with hydronephrosis and TBS2 features. During murine development, Dact1 was expressed in organs affected by anomalies in patients with DACT1 variants, including the kidney, anal canal, vertebrae, and brain. In a branching morphogenesis assay, tubule formation was impaired in CRISPR/Cas9-induced Dact1
Identifiants
pubmed: 36066768
doi: 10.1007/s00439-022-02481-6
pii: 10.1007/s00439-022-02481-6
pmc: PMC9839807
doi:
Substances chimiques
DACT1 protein, human
0
Nuclear Proteins
0
Adaptor Proteins, Signal Transducing
0
DVL2 protein, human
0
Dishevelled Proteins
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
73-88Subventions
Organisme : Deutsche Forschungsgemeinschaft
ID : KO5614/2-1
Organisme : Deutsche Forschungsgemeinschaft
ID : MA9606/1-1
Informations de copyright
© 2022. The Author(s).
Références
Kidney Int. 2019 Apr;95(4):914-928
pubmed: 30773290
Nat Rev Genet. 2007 Oct;8(10):791-802
pubmed: 17878895
Pediatr Nephrol. 2012 Mar;27(3):363-73
pubmed: 21713524
Hum Mutat. 2017 Apr;38(4):373-377
pubmed: 28054444
Nucleic Acids Res. 2019 Jan 8;47(D1):D886-D894
pubmed: 30371827
Kidney Int. 2022 May;101(5):1039-1053
pubmed: 35227688
Eur J Med Genet. 2014 Jul;57(7):322-8
pubmed: 24821302
N Engl J Med. 2013 Aug 15;369(7):621-9
pubmed: 23862974
Am J Hum Genet. 2020 Oct 1;107(4):727-742
pubmed: 32891193
Semin Cell Dev Biol. 2019 Jul;91:104-110
pubmed: 30172048
J Am Soc Nephrol. 2018 Sep;29(9):2348-2361
pubmed: 30143558
Kidney Int. 2002 Jan;61(1):10-9
pubmed: 11786080
Kidney Int. 2016 Feb;89(2):476-86
pubmed: 26489027
Development. 2009 Jan;136(1):161-71
pubmed: 19060336
Hum Genet. 2016 Jan;135(1):69-87
pubmed: 26572137
J Am Soc Nephrol. 2018 Jan;29(1):36-50
pubmed: 29079659
Mol Biol Cell. 2005 Sep;16(9):4398-409
pubmed: 15975909
Development. 2012 Sep;139(17):3099-108
pubmed: 22833126
Reprod Biomed Online. 2016 Apr;32(4):420-6
pubmed: 26856455
J Clin Invest. 2018 Jan 2;128(1):4-15
pubmed: 29293093
Genetics. 2017 Sep;207(1):215-228
pubmed: 28739660
Prog Mol Biol Transl Sci. 2018 Jan;153:181-207
pubmed: 29389516
Am J Hum Genet. 2017 Nov 2;101(5):803-814
pubmed: 29100091
Nat Genet. 2019 Jan;51(1):117-127
pubmed: 30578417
J Biol Chem. 2006 Mar 31;281(13):8607-12
pubmed: 16446366
Kidney Int. 2014 Jun;85(6):1429-33
pubmed: 24429398
J Am Soc Nephrol. 2013 Mar;24(4):550-8
pubmed: 23520208
Am J Hum Genet. 2008 Jan;82(1):39-47
pubmed: 18179883
Am J Physiol Renal Physiol. 2004 Oct;287(4):F602-11
pubmed: 15187002
Am J Hum Genet. 2015 Aug 6;97(2):291-301
pubmed: 26235987
Genet Med. 2015 May;17(5):405-24
pubmed: 25741868
Commun Integr Biol. 2013 Nov 1;6(6):e26834
pubmed: 24505507
Am J Med Genet A. 2021 Oct;185(10):3005-3011
pubmed: 34145744
Hum Mutat. 2012 Oct;33(10):1450-5
pubmed: 22610794
Am J Nephrol. 2017;46(1):55-63
pubmed: 28618409
Nat Genet. 2009 Sep;41(9):977-85
pubmed: 19701191
Dev Cell. 2002 Apr;2(4):449-61
pubmed: 11970895
J Histochem Cytochem. 2001 Jan;49(1):1-8
pubmed: 11118473
Arch Gynecol Obstet. 2002 Jul;266(3):163-7
pubmed: 12197558
Nat Genet. 2014 Mar;46(3):310-5
pubmed: 24487276
Hum Mol Genet. 2014 Dec 20;23(25):6807-14
pubmed: 25082826
Kidney Int. 2020 Oct;98(4):1020-1030
pubmed: 32450157
Eur J Hum Genet. 2020 Dec;28(12):1681-1693
pubmed: 32737436
Am J Hum Genet. 2014 Feb 6;94(2):288-94
pubmed: 24439109
J Biol Chem. 2010 Apr 2;285(14):11023-30
pubmed: 20145239
Hum Mol Genet. 2020 May 8;29(7):1192-1204
pubmed: 32179912
Pediatr Nephrol. 2014 Apr;29(4):737-44
pubmed: 24445433
J Mol Med (Berl). 2020 Nov;98(11):1511-1523
pubmed: 32939578
Nat Protoc. 2013 Nov;8(11):2281-2308
pubmed: 24157548
Hum Mol Genet. 2017 May 1;26(9):1716-1731
pubmed: 28334964
Nat Methods. 2012 Jul;9(7):671-5
pubmed: 22930834
Nat Genet. 1998 Jan;18(1):81-3
pubmed: 9425907
J Am Soc Nephrol. 2017 Oct;28(10):2901-2914
pubmed: 28566479
Organogenesis. 2008 Apr;4(2):55-9
pubmed: 19279716
Organogenesis. 2014 Jan 1;10(1):86-95
pubmed: 24162855
Nephrol Dial Transplant. 2011 Jan;26(1):136-43
pubmed: 20605837