Monoallelic pathogenic ALG5 variants cause atypical polycystic kidney disease and interstitial fibrosis.
ALG5
N-linked glycosylation
autosomal dominant tubulo-interstitial kidney disease
autosomal-dominant polycystic kidney disease
renal insufficiency
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 08 2022
04 08 2022
Historique:
received:
11
03
2022
accepted:
23
06
2022
pubmed:
28
7
2022
medline:
10
8
2022
entrez:
27
7
2022
Statut:
ppublish
Résumé
Disorders of the autosomal dominant polycystic kidney disease (ADPKD) spectrum are characterized by the development of kidney cysts and progressive kidney function decline. PKD1 and PKD2, encoding polycystin (PC)1 and 2, are the two major genes associated with ADPKD; other genes include IFT140, GANAB, DNAJB11, and ALG9. Genetic testing remains inconclusive in ∼7% of the families. We performed whole-exome sequencing in a large multiplex genetically unresolved (GUR) family affected by ADPKD-like symptoms and identified a monoallelic frameshift variant (c.703_704delCA) in ALG5. ALG5 encodes an endoplasmic-reticulum-resident enzyme required for addition of glucose molecules to the assembling N-glycan precursors. To identify additional families, we screened a cohort of 1,213 families with ADPKD-like and/or autosomal-dominant tubulointerstitial kidney diseases (ADTKD), GUR (n = 137) or naive to genetic testing (n = 1,076), by targeted massively parallel sequencing, and we accessed Genomics England 100,000 Genomes Project data. Four additional families with pathogenic variants in ALG5 were identified. Clinical presentation was consistent in the 23 affected members, with non-enlarged cystic kidneys and few or no liver cysts; 8 subjects reached end-stage kidney disease from 62 to 91 years of age. We demonstrate that ALG5 haploinsufficiency is sufficient to alter the synthesis of the N-glycan chain in renal epithelial cells. We also show that ALG5 is required for PC1 maturation and membrane and ciliary localization and that heterozygous loss of ALG5 affects PC1 maturation. Overall, our results indicate that monoallelic variants of ALG5 lead to a disorder of the ADPKD-spectrum characterized by multiple small kidney cysts, progressive interstitial fibrosis, and kidney function decline.
Identifiants
pubmed: 35896117
pii: S0002-9297(22)00266-X
doi: 10.1016/j.ajhg.2022.06.013
pmc: PMC9388391
pii:
doi:
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1484-1499Subventions
Organisme : NIDDK NIH HHS
ID : R01 DK058816
Pays : United States
Informations de copyright
Copyright © 2022 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests The authors declare no competing interests.
Références
Nat Rev Mol Cell Biol. 2020 Dec;21(12):729-749
pubmed: 33087899
Nephrol Dial Transplant. 2022 Jan 25;37(2):239-254
pubmed: 34264297
Cell. 1996 Dec 13;87(6):979-87
pubmed: 8978603
J Clin Invest. 2017 Sep 1;127(9):3558
pubmed: 28862642
Proc Natl Acad Sci U S A. 2005 Apr 26;102(17):5913-9
pubmed: 15755804
Kidney Int. 2022 Jun;101(6):1126-1141
pubmed: 35460632
Kidney Int. 2015 Oct;88(4):676-83
pubmed: 25738250
Nat Rev Mol Cell Biol. 2019 Jul;20(7):421-435
pubmed: 30733602
J Clin Invest. 2017 Nov 1;127(11):3954-3969
pubmed: 28990932
Methods Cell Biol. 2013;118:157-76
pubmed: 24295306
Nat Rev Dis Primers. 2018 Dec 6;4(1):50
pubmed: 30523303
Nat Genet. 2004 Jun;36(6):575-7
pubmed: 15133510
J Am Soc Nephrol. 2019 Nov;30(11):2091-2102
pubmed: 31395617
J Am Soc Nephrol. 2016 Mar;27(3):942-51
pubmed: 26150605
Nat Genet. 2003 Mar;33(3):345-7
pubmed: 12577059
Proc Natl Acad Sci U S A. 1999 Jun 8;96(12):6982-7
pubmed: 10359825
J Biol Chem. 2002 Jun 7;277(23):20763-73
pubmed: 11901144
Clin Gastroenterol Hepatol. 2013 Dec;11(12):1609-13
pubmed: 23856358
J Am Soc Nephrol. 2018 Oct;29(10):2482-2492
pubmed: 30185468
Nature. 2020 May;581(7809):434-443
pubmed: 32461654
Lancet. 2019 Mar 2;393(10174):919-935
pubmed: 30819518
J Am Soc Nephrol. 2018 Aug;29(8):2139-2156
pubmed: 30042192
J Am Soc Nephrol. 2018 Jun;29(6):1583-1584
pubmed: 29769229
J Biol Chem. 2014 May 23;289(21):14854-67
pubmed: 24719335
Am J Hum Genet. 2018 May 3;102(5):832-844
pubmed: 29706351
Nat Genet. 1995 Jun;10(2):151-60
pubmed: 7663510
J Am Soc Nephrol. 2018 Jan;29(1):13-23
pubmed: 29038287
Nat Rev Dis Primers. 2019 Sep 5;5(1):60
pubmed: 31488840
Kidney Int. 2015 Oct;88(4):699-710
pubmed: 26200945
Am J Hum Genet. 2016 Jun 2;98(6):1193-1207
pubmed: 27259053
Nat Commun. 2014 Nov 18;5:5482
pubmed: 25405894
Nat Rev Dis Primers. 2020 Mar 26;6(1):20
pubmed: 32218442
Kidney Int. 2020 Aug;98(2):476-487
pubmed: 32631624
Ann Intern Med. 2009 May 5;150(9):604-12
pubmed: 19414839
J Biol Chem. 1999 Oct 1;274(40):28557-65
pubmed: 10497221
Annu Rev Biochem. 2004;73:1019-49
pubmed: 15189166
Nat Rev Nephrol. 2014 Jul;10(7):369-78
pubmed: 24752014
J Am Soc Nephrol. 2017 Aug;28(8):2529-2539
pubmed: 28373276
PLoS One. 2017 Apr 24;12(4):e0175970
pubmed: 28437467
Am J Hum Genet. 2022 Jan 6;109(1):136-156
pubmed: 34890546
J Am Soc Nephrol. 2016 Sep;27(9):2872-84
pubmed: 26823553
J Clin Invest. 2012 Nov;122(11):4257-73
pubmed: 23064367
Mol Cell. 1998 Aug;2(2):247-51
pubmed: 9734362
Kidney Int. 2018 May;93(5):1045-1051
pubmed: 29551517
J Clin Invest. 2015 Feb;125(2):607-20
pubmed: 25574838
Eur J Biochem. 1994 Aug 15;224(1):71-9
pubmed: 8076653
J Am Soc Nephrol. 2021 Oct 29;:
pubmed: 34716216
Am J Hum Genet. 2021 Jan 7;108(1):8-15
pubmed: 33417889