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 Figueroa; Ricard 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

doi:10.1016/j.xcrm.2021.100475

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

Cell Rep Med. 2021 Dec 21;2(12):100475. doi: 10.1016/j.xcrm.2021.100475.

Authors

Simon H Jiang^{1

2

3}, Sevcan Mercan^{1

4}, Ilenia Papa¹, Max Moldovan^{5

6}, Giles D Walters³, Mark Koina⁷, Mitali Fadia⁷, Maurice Stanley¹, Tom Lea-Henry¹, Amelia Cook¹, Julia Ellyard^{1

2}, Brendan McMorran¹, Madhivanan Sundaram⁸, Russell Thomson⁹, Pablo F Canete^{1

2}, Wendy Hoy¹⁰, Holly Hutton¹¹, Monika Srivastava¹, Kathryn McKeon^{1

2}, Iñigo de la Rúa Figueroa¹², Ricard Cervera¹³, Raquel Faria¹⁴, Sandra D'Alfonso¹⁵, Mariele Gatto¹⁶, Vicki Athanasopoulos^{1

2}, Matthew Field¹⁷, John Mathews¹⁸, Eun Cho¹⁹, Thomas D Andrews¹⁹, A Richard Kitching^{11

20}, Matthew C Cook²¹, Marta Alarcon Riquelme²², Melanie Bahlo^{23

24}, Carola G Vinuesa^{1

2

25

26}

Affiliations

¹ Department of Immunology and Infectious Disease, John Curtin School of Medical Research, Canberra, Australian National University, Canberra 2601, Australia.
² Centre for Personalised Immunology, NHMRC Centre for Research Excellence, Australian National University, Canberra 2601, Australia.
³ Department of Renal Medicine, The Canberra Hospital, Canberra 2605, Australia.
⁴ Department of Bioengineering, Kafkas University, Kars 36100, Turkey.
⁵ Centre for Population Health Research, University of South Australia, South Australian Health and Medical Research Institute (SAHMRI), Adelaide 5001, Australia.
⁶ Australian Institute of Health Innovation, Macquarie University, Sydney 2109, Australia.
⁷ Department of Pathology, The Canberra Hospital, Canberra 2605, Australia.
⁸ Department of Renal Medicine, Royal Darwin Hospital, Northern Territory 0811, Australia.
⁹ Centre for Research in Mathematics and Data Science, School of Computer, Data and Mathematical Sciences, Western Sydney University, Parramatta 2150, NSW, Australia.
¹⁰ Centre for Chronic Disease, Faculty of Health, The University of Queensland, Brisbane 4029, QLD, Australia.
¹¹ Centre for Inflammatory Diseases, Monash University, Melbourne 3168, VIC, Australia.
¹² University Hospital of Gran Canaria Dr. Negrin, Las Palmas 35010, Spain.
¹³ Department of Autoimmune Diseases, Hospital Clinic, Barcelona 08036, Spain.
¹⁴ Unidade de Imunologia Clinica, Centro Hospitalar Unisersitario do Porto, Porto 4099-001, Portugal.
¹⁵ Amedeo Avogadro University of East Piedmont 13100, Italy.
¹⁶ Department of Rheumatology, University of Padova, Italy.
¹⁷ Australian Institute of Tropical Health and Medicine, James Cook University, Cairns 4870, QLD, Australia.
¹⁸ School of Population and Global Health, University of Melbourne, Melbourne 3053, Australia.
¹⁹ Genome Informatics Laboratory, John Curtin School of Medical Research, Australian National University, Canberra 2601, Australia.
²⁰ Departments Nephrology and Paediatric Nephrology. Monash Health, Melbourne 3168, Australia.
²¹ Department of Immunology, The Canberra Hospital, Canberra 2605, Australia.
²² Department of Medical Genomics, GENYO. Centre for Genomics and Oncological Research: Pfizer/University of Granada/Andalusian Regional Government, Granada, 18016, Spain.
²³ Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne 3052, Australia.
²⁴ Department of Medical Biology, The University of Melbourne, Parkville 3010 VIC, Australia.
²⁵ China Australia Centre for Personalised Immunology, Renji Hospital Shanghai, JiaoTong University Shanghai 200001, China.
²⁶ Francis Crick Institute, 1 Midland Rd, London NW1 1AT, UK.

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.

Keywords: antibody; autoimmune; chronic kidney disease; genetic; glomerulonephritis; immunoglobulin; lupus nephritis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Aged
Animals
Antibodies / adverse effects*
Biopsy
Carrier Proteins / genetics*
Cohort Studies
DNA Copy Number Variations / genetics
Gene Deletion*
Homozygote
Humans
Introns / genetics
Kidney / metabolism
Kidney / pathology
Kidney Diseases / pathology*
Lupus Nephritis / genetics
Membrane Proteins / deficiency
Membrane Proteins / genetics*
Membrane Proteins / metabolism
Mice
Mice, Inbred C57BL
Mice, Knockout
Middle Aged
Risk Factors

Substances

Antibodies
Carrier Proteins
Membrane Proteins
VANGL1 protein, human
Vangl1 protein, mouse