Basement membrane defects in CD151-associated glomerular disease.
CD151
Glomerular Basement Membrane
Kidney disease
MER2 Podocyte
Proteinuria
Journal
Pediatric nephrology (Berlin, Germany)
ISSN: 1432-198X
Titre abrégé: Pediatr Nephrol
Pays: Germany
ID NLM: 8708728
Informations de publication
Date de publication:
12 2022
12 2022
Historique:
received:
27
08
2021
accepted:
12
01
2022
revised:
12
01
2022
pubmed:
13
3
2022
medline:
26
10
2022
entrez:
12
3
2022
Statut:
ppublish
Résumé
CD151 is a cell-surface molecule of the tetraspanin family. Its lateral interaction with laminin-binding integrin ɑ3β1 is important for podocyte adhesion to the glomerular basement membrane (GBM). Deletion of Cd151 in mice induces glomerular dysfunction, with proteinuria and associated focal glomerulosclerosis, disorganisation of GBM and tubular cystic dilation. Despite this, CD151 is not routinely screened for in patients with nephrotic-range proteinuria. We aimed to better understand the relevance of CD151 in human kidney disease. Next-generation sequencing (NGS) was used to detect the variant in CD151. Electron and light microscopy were used to visualise the filtration barrier in the patient kidney biopsy, and immunoreactivity of patient red blood cells to anti-CD151/MER2 antibodies was performed. Further validation of the CD151 variant as disease-causing was performed in zebrafish using CRISPR-Cas9. We report a young child with nail dystrophy and persistent urinary tract infections who was incidentally found to have nephrotic-range proteinuria. Through targeted NGS, a novel, homozygous truncating variant was identified in CD151, a gene rarely reported in patients with nephrotic syndrome. Electron microscopy imaging of patient kidney tissue showed thickening of GBM and podocyte effacement. Immunofluorescence of patient kidney tissue demonstrated that CD151 was significantly reduced, and we did not detect immunoreactivity to CD151/MER2 on patient red blood cells. CRISPR-Cas9 depletion of cd151 in zebrafish caused proteinuria, which was rescued by injection of wild-type CD151 mRNA, but not CD151 mRNA containing the variant sequence. Our results indicate that a novel variant in CD151 is associated with nephrotic-range proteinuria and microscopic haematuria and provides further evidence for a role of CD151 in glomerular disease. Our work highlights a functional testing pipeline for future analysis of patient genetic variants. A higher resolution version of the Graphical abstract is available as Supplementary information.
Sections du résumé
BACKGROUND
CD151 is a cell-surface molecule of the tetraspanin family. Its lateral interaction with laminin-binding integrin ɑ3β1 is important for podocyte adhesion to the glomerular basement membrane (GBM). Deletion of Cd151 in mice induces glomerular dysfunction, with proteinuria and associated focal glomerulosclerosis, disorganisation of GBM and tubular cystic dilation. Despite this, CD151 is not routinely screened for in patients with nephrotic-range proteinuria. We aimed to better understand the relevance of CD151 in human kidney disease.
METHODS
Next-generation sequencing (NGS) was used to detect the variant in CD151. Electron and light microscopy were used to visualise the filtration barrier in the patient kidney biopsy, and immunoreactivity of patient red blood cells to anti-CD151/MER2 antibodies was performed. Further validation of the CD151 variant as disease-causing was performed in zebrafish using CRISPR-Cas9.
RESULTS
We report a young child with nail dystrophy and persistent urinary tract infections who was incidentally found to have nephrotic-range proteinuria. Through targeted NGS, a novel, homozygous truncating variant was identified in CD151, a gene rarely reported in patients with nephrotic syndrome. Electron microscopy imaging of patient kidney tissue showed thickening of GBM and podocyte effacement. Immunofluorescence of patient kidney tissue demonstrated that CD151 was significantly reduced, and we did not detect immunoreactivity to CD151/MER2 on patient red blood cells. CRISPR-Cas9 depletion of cd151 in zebrafish caused proteinuria, which was rescued by injection of wild-type CD151 mRNA, but not CD151 mRNA containing the variant sequence.
CONCLUSIONS
Our results indicate that a novel variant in CD151 is associated with nephrotic-range proteinuria and microscopic haematuria and provides further evidence for a role of CD151 in glomerular disease. Our work highlights a functional testing pipeline for future analysis of patient genetic variants. A higher resolution version of the Graphical abstract is available as Supplementary information.
Identifiants
pubmed: 35278129
doi: 10.1007/s00467-022-05447-y
pii: 10.1007/s00467-022-05447-y
pmc: PMC9587066
doi:
Substances chimiques
CD151 protein, human
0
Integrin alpha3beta1
0
Laminin
0
RNA, Messenger
0
Tetraspanin 24
0
Types de publication
Case Reports
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3105-3115Subventions
Organisme : Wellcome Trust
Pays : United Kingdom
Informations de copyright
© 2022. The Author(s).
Références
Matrix Biol. 2018 Mar;66:22-33
pubmed: 29138120
J Cell Biol. 2006 Oct 9;175(1):33-9
pubmed: 17015618
J Cell Sci. 2002 Mar 15;115(Pt 6):1161-73
pubmed: 11884516
Nat Struct Mol Biol. 2009 Feb;16(2):107-13
pubmed: 19190664
Dev Cell. 2018 Jul 2;46(1):112-125.e4
pubmed: 29974860
Cell Mol Life Sci. 2001 Aug;58(9):1189-205
pubmed: 11577978
Am J Pathol. 2008 Oct;173(4):927-37
pubmed: 18787104
Blood. 2004 Oct 15;104(8):2217-23
pubmed: 15265795
Proc Natl Acad Sci U S A. 2017 Mar 14;114(11):2958-2963
pubmed: 28246329
Kidney Int. 1998 Sep;54(3):687-97
pubmed: 9734594
J Biol Chem. 2001 Nov 2;276(44):41165-74
pubmed: 11479292
Nat Protoc. 2015 Jun;10(6):845-58
pubmed: 25950237
Nat Metab. 2020 May;2(5):461-474
pubmed: 32694662
PLoS One. 2012;7(9):e45286
pubmed: 23028906
Kidney Int. 2002 Sep;62(3):895-900
pubmed: 12164871
Am J Physiol Renal Physiol. 2015 Sep 15;309(6):F531-9
pubmed: 26202224
Kidney Int. 2017 Apr;91(4):937-947
pubmed: 28117080
J Clin Invest. 2012 Jan;122(1):348-58
pubmed: 22201679
Dev Dyn. 1995 Jul;203(3):253-310
pubmed: 8589427
Genet Med. 2015 May;17(5):405-24
pubmed: 25741868
Mol Biol Cell. 1998 Oct;9(10):2751-65
pubmed: 9763442
Kidney Int. 2022 Oct;102(4):815-827
pubmed: 35716957
Methods Cell Biol. 2010;100:233-60
pubmed: 21111220
J Clin Invest. 2012 Jan;122(1):13-6
pubmed: 22201676