Loss of GalNAc-T14 links O-glycosylation defects to alterations in B cell homing in IgA nephropathy
Sindhuri Prakash, … , Jan Novak, Ali G. Gharavi
Sindhuri Prakash, … , Jan Novak, Ali G. Gharavi
Published March 28, 2025
Citation Information: J Clin Invest. 2025;135(10):e181164. https://doi.org/10.1172/JCI181164.
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Research Article Genetics Nephrology

Loss of GalNAc-T14 links O-glycosylation defects to alterations in B cell homing in IgA nephropathy

Abstract

Aberrant O-glycosylation of the IgA1 hinge region is a characteristic finding in patients with IgA nephropathy (IgAN) and is thought to contribute to immune-complex formation and kidney injury. Other studies have suggested that abnormalities in mucosal immunity and lymphocyte homing are major contributors to disease. We identified a family with IgAN segregating a heterozygous predicted loss-of-function (LOF) variant in GALNT14, the gene encoding N-acetylgalactosaminyltransferase 14, one of the enzymes involved in mucin-type protein O-glycosylation. While GALNT14 is expressed in IgA1-producing cells, carriers of the LOF variant did not have altered levels of poorly glycosylated IgA1, suggesting other disease mechanisms. Investigation of Galnt14-null mice revealed elevated serum IgA levels and ex vivo IgA production by B cells. These mice developed glomerular IgA deposition with aging and after induction of sterile colitis. Galnt14-null mice also displayed an attenuated mucin layer in the colon and redistribution of IgA-producing cells from mucosal to systemic sites. Adoptive-transfer experiments indicated impaired homing of spleen-derived Galnt14-deficient B lymphocytes, resulting in increased retention in peripheral blood. These findings suggest that abnormalities in O-glycosylation alter mucosal immunity and B lymphocyte homing, pointing to an expanded role of aberrant O-glycosylation in the pathogenesis of IgAN.

Authors

Sindhuri Prakash, Nicholas J. Steers, Yifu Li, Elena Sanchez-Rodriguez, Miguel Verbitsky, Isabel Robbins, Jenna Simpson, Sharvari Pathak, Milan Raska, Colin Reily, Anna Ng, Judy Liang, Natalia DeMaria, Amanda Katiraei, Kelsey O. Stevens, Clara Fischman, Samantha Shapiro, Swetha Kodali, Jason McCutchan, Heekuk Park, Djamila Eliby, Marco Delsante, Landino Allegri, Enrico Fiaccadori, Monica Bodria, Maddalena Marasa, Elizabeth Raveche, Bruce A. Julian, Anne-Catrin Uhlemann, Krzysztof Kiryluk, Hong Zhang, Vivette D. D’Agati, Simone Sanna-Cherchi, Jan Novak, Ali G. Gharavi

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Figure 7

Adoptive transfer of lymphocytes from Galnt14–/– mice demonstrates a deficiency in the homing ability of B cells.

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Adoptive transfer of lymphocytes from Galnt14–/– mice demonstrates a def...
(A) Schematic of the adoptive transfer experiment. (B) Identification of the adoptively transferred B cells in the spleen and the peripheral blood of the recipient mice. (C) Adoptive transfer of 3.5 × 106 lymphocytes derived from Galnt14–/– mice had significantly less (P < 0.01, unpaired t test) CD19+ B cells identified in the spleens of the recipient mice (Galnt14+/+ or Galnt14–/–, n = 5 per group, 2 male and 3 female) compared with adoptively transferred lymphocytes derived from Galnt14+/+ mice into recipient mice (Galnt14+/+ or Galnt14–/–, n = 5 per group). (D) Adoptive transfer of 3.5 × 106 lymphocytes derived from Galnt14–/– mice had increased (P < 0.01) CD19+ B cells identified in the PBMC of the recipient mice (Galnt14+/+ or Galnt14–/–, n = 5 per group) compared with adoptively transferred lymphocytes derived from Galnt14+/+ mice into the recipient mice (Galnt14+/+ or Galnt14–/–, n = 5 per group, 2 male and 3 female).