Deletions in VANGL1 are a risk factor for antibody-mediated kidney disease

Simon H. Jiang, Sevcan Mercan, Ilenia Papa, Max Moldovan, Giles D. Walters, Mark Koina, Mitali Fadia, Maurice Stanley, Tom Lea-Henry, Amelia Cook, Julia Ellyard, Brendan McMorran, Madhivanan Sundaram, Russell Thomson, Pablo F. Canete, Wendy Hoy, Holly Hutton, Monika Srivastava, Kathryn McKeon, Iñigo de la Rúa FigueroaRicard Cervera, Raquel Faria, Sandra D'Alfonso, Mariele Gatto, Vicki Athanasopoulos, Matthew Field, John Mathews, Eun Cho, Thomas D. Andrews, A. Richard Kitching, Matthew C. Cook, Marta Alarcon Riquelme, Melanie Bahlo, Carola G. Vinuesa*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)
16 Downloads (Pure)

Abstract

We identify an intronic deletion in VANGL1 that predisposes to renal injury in high risk populations through a kidney-intrinsic process. Half of all SLE patients develop nephritis, yet the predisposing mechanisms to kidney damage remain poorly understood. There is limited evidence of genetic contribution to specific organ involvement in SLE.1,2 We identify a large deletion in intron 7 of Van Gogh Like 1 (VANGL1), which associates with nephritis in SLE patients. The same deletion occurs at increased frequency in an indigenous population (Tiwi Islanders) with 10-fold higher rates of kidney disease compared with non-indigenous populations. Vangl1 hemizygosity in mice results in spontaneous IgA and IgG deposition within the glomerular mesangium in the absence of autoimmune nephritis. Serum transfer into B cell-deficient Vangl1+/− mice results in mesangial IgG deposition indicating that Ig deposits occur in a kidney-intrinsic fashion in the absence of Vangl1. These results suggest that Vangl1 acts in the kidney to prevent Ig deposits and its deficiency may trigger nephritis in individuals with SLE.

Original languageEnglish
Article number100475
Pages (from-to)1-10
Number of pages14
JournalCell Reports Medicine
Volume2
Issue number12
DOIs
Publication statusPublished - 21 Dec 2021

Bibliographical note

Copyright the Author(s)2021. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

Keywords

  • antibody
  • autoimmune
  • chronic kidney disease
  • genetic
  • glomerulonephritis
  • immunoglobulin
  • lupus nephritis

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