Kidney Week

Abstract: TH-PO0398

Genetic and Functional Studies Define OVOL1 as a New Regulator of IgA1 O-Glycosylation

Session Information

• Glomerular Diseases: Autoimmune Diseases
  October 22, 2026 | Location: Exhibit Hall A, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Glomerular Diseases

• 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology

Authors

• Liu, Lili, University of Michigan, Ann Arbor, Michigan, United States

Lili Liu, PhD

• Zhou, Xujie, Peking University First Hospital, Beijing, China

Xujie Zhou, MD, PhD

• Kravets, Oleksandr, Columbia University, New York, New York, United States

Oleksandr Kravets, MS, PhD

• Khan, Atlas, Columbia University, New York, New York, United States

Atlas Khan, MS, PhD, FASN

• Qiu, Shihong, The University of Alabama at Birmingham Department of Medicine, Birmingham, Alabama, United States

Shihong Qiu

• Shang, Qiao, The University of Alabama at Birmingham Department of Medicine, Birmingham, Alabama, United States

Qiao Shang

• Moldoveanu, Zina, The University of Alabama at Birmingham Department of Medicine, Birmingham, Alabama, United States

Zina Moldoveanu, PhD

• Reily, Colin, The University of Alabama at Birmingham Department of Medicine, Birmingham, Alabama, United States

Colin Reily, PhD

• Schou, Olivia, The University of Alabama at Birmingham Department of Medicine, Birmingham, Alabama, United States

Olivia Schou

• Cunningham, Mary A., The University of Alabama at Birmingham Department of Medicine, Birmingham, Alabama, United States

Mary A. Cunningham, PhD

• Knoppova, Barbora, The University of Alabama at Birmingham Department of Medicine, Birmingham, Alabama, United States

Barbora Knoppova, MS

• Hall, Stacy D., The University of Alabama at Birmingham Department of Medicine, Birmingham, Alabama, United States

Stacy D. Hall, MPH

• Nakazawa, Shigeaki, The University of Alabama at Birmingham Department of Medicine, Birmingham, Alabama, United States

Shigeaki Nakazawa, MD, PhD

• Kamata, Masakazu, The University of Alabama at Birmingham Department of Medicine, Birmingham, Alabama, United States

Masakazu Kamata, DrPH

• Hirayama, Masaya, The University of Alabama at Birmingham Department of Medicine, Birmingham, Alabama, United States

Masaya Hirayama, PhD

• King, Rodney G., The University of Alabama at Birmingham Department of Medicine, Birmingham, Alabama, United States

Rodney G. King, PhD

• Julian, Bruce A., The University of Alabama at Birmingham Department of Medicine, Birmingham, Alabama, United States

Bruce A. Julian, MD

• Rizk, Dana V., The University of Alabama at Birmingham Department of Medicine, Birmingham, Alabama, United States

Dana V. Rizk, MD

• Falchi, Mario, King's College London, London, England, United Kingdom

Mario Falchi, PhD

• Zhang, Hong, Peking University First Hospital, Beijing, China

Hong Zhang, MD, PhD

• Renfrow, Matthew B., The University of Alabama at Birmingham Department of Medicine, Birmingham, Alabama, United States

Matthew B. Renfrow, PhD

• Green, Todd J., The University of Alabama at Birmingham Department of Medicine, Birmingham, Alabama, United States

Todd J. Green, PhD

• Gharavi, Ali G., Columbia University, New York, New York, United States

Ali G. Gharavi, MD

• Novak, Jan, The University of Alabama at Birmingham Department of Medicine, Birmingham, Alabama, United States

Jan Novak, PhD

• Kiryluk, Krzysztof, Columbia University, New York, New York, United States

Krzysztof Kiryluk, MD

Background

Galactose (Gal)-deficient IgA1 (Gd-IgA1) is a putative pathogenic factor in IgA nephropathy (IgAN). Circulating Gd-IgA1 is recognized by IgG autoantibodies to form pathogenic immune complexes, which deposit in glomeruli, activate mesangial cells, and induce kidney injury.

Methods

Genome-wide association study (GWAS) for serum Gd-IgA1 levels in 12,700 participants across 21 diverse international cohorts included 2,615 IgAN patients and 10,085 controls. Co-localizations used COLOC. Paired VH-VL genes from a single IgA1-producing cell clone were used for expression of recombinant polymeric IgA1 in Expi293F cells. Gd-IgA1 standard was produced in C1GALT1-KO Expi293F cells. We tested whether overexpression of OVOL1 or its isoform OVOL1/X1 affected production of Gd-IgA1, expression of C1GALT1 and C1GALT1C1 genes, and IgA1 O-glycosylation patterns using plasmid co-transfection, lectin ELISA, SDS–PAGE western blotting, qPCR, and quantitative mass spectrometry. Four independent experiments were performed to enable statistical evaluation.

Results

GWAS of serum Gd-IgA1 levels identified OVOL1 locus as the strongest new genome-wide significant signal (rs10896045-A, beta=0.12, P=1.7x10^-18). This locus co-localized (PP4 >0.99) with GWAS locus for IgAN, serum IgA levels, and multiple patterns of IgG N-glycosylation. Overexpression of OVOL1 or OVOL1/X1 in Expi293F cells increased Gal deficiency of secreted IgA1, as determined by lectin ELISA (P=0.0002 and P<0.0001, respectively) and confirmed by lectin western blotting, whereas GFP-encoding and empty-vector controls had no effect. Quantitative mass spectrometry of IgA1 hinge-region glycopeptides showed that OVOL1 or OVOL1/X1 overexpression markedly shifted O-glycosylation profiles. Control IgA1 included glycoforms with Gal (GalNAc₄Gal₄, 16.7%; GalNAc₅Gal₄, 12.9%) and without Gal (16.4% for GalNAc_1-4). OVOL1 and OVOL1/X1 overexpression reduced GalNAc₄Gal₄ from 16.7% in controls to 8.05% and 5.26%, respectively, and increased GalNAc_1-4 from 16.4% in controls to 54.7%. qPCR showed that OVOL1 or OVOL1/X1 overexpression reduced expression of C1GALT1, the enzyme responsible for adding Gal to GalNAc of IgA1 O-glycans.

Conclusion

Our findings provide new insights into the genetic regulation of serum Gd-IgA1 levels and nominate OVOL1 as a novel regulator of IgA1 O-glycosylation.