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.
View: Text | PDF
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

×

Figure 1

Genetic variation of GALNT14 in familial IgAN and expression in lymphoid tissues.

Options: View larger image (or click on image) Download as PowerPoint
Genetic variation of GALNT14 in familial IgAN and expression in lymphoid...
(A) A pedigree with 2 individuals with biopsy-proven IgAN (individuals with corresponding phenotype are indicated). Exome sequencing was performed in individuals with an asterisk (*) (the proband and his mother). Genome-wide genotyping was performed on all individuals with available DNA, denoted by red circles. Individuals carrying the GALNT14 nonsense variant are denoted by a fully filled-in red dot, confirmed by Sanger sequencing. (B) Logarithm of odds (LOD) score plot for parametric linkage analysis under the autosomal dominant model with incomplete penetrance revealed 7 top signals (totaling about 2.4% of the genome) harboring about 1,800 genes, including the nonsense variant (p.R315X) found in GALNT14. (C) Confirmatory Sanger sequencing was done in all individuals with available DNA. Representative chromatograms are shown here with corresponding amino acid sequence. (D) No differences in the total IgA serum levels between the variant carriers and noncarriers (denoted as reference). (E) No differences in Gd-IgA1 levels between carriers and noncarriers of the p.R315X variant. (F) Sanger sequencing of sporadic IgAN cases of revealed an additional patient with a nonsense variant resulting in a premature termination of translation (representative chromatogram and amino acid sequence is shown). (G) IHC of GalNAc-T14 in the human spleen (n = 1), (H) human lymph node (n = 1), (I) human kidney cortex (n = 1). (J) human kidney medulla (n = 1). (K) human proximal and distal tubules of the kidney (n = 1). (L) Human kidney glomerulus (n = 1), (M) Comparison of the expression of different N-acetylgalactosaminyltransferases in immortalized IgA1-secreting cell lines demonstrates elevated expression of GALNT14 in the cells derived from the peripheral blood of patients with IgAN (n = 4) compared with those from healthy individuals (n = 4) (*P = 0.006). Original magnification, ×200 (G and H), ×400 (I—L).