Deletions in <i>VANGL1</i> are a risk factor for antibody-mediated kidney disease.

Abstract

We identify an intronic deletion in <i>VANGL1</i> 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 <i>Van Gogh Like 1</i> (<i>VANGL1</i>), 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. <i>Vangl1</i> 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 <i>Vangl1</i>^<i>+/-</i> mice results in mesangial IgG deposition indicating that Ig deposits occur in a kidney-intrinsic fashion in the absence of <i>Vangl1</i>. These results suggest that <i>Vangl1</i> acts in the kidney to prevent Ig deposits and its deficiency may trigger nephritis in individuals with SLE.