Sharvari Pathak

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.