Novel pathogenic MAN2B2 variants cause systemic lupus erythematosus and dysregulated glycosylation.

Genetic factors have been demonstrated to play essential roles in the pathogenesis of systemic lupus erythematosus (SLE). Identifying novel disease-causing genes of SLE helps to reveal its molecular mechanisms and new therapeutic targets. In this study, we identified biallelic loss-of-function variants of MAN2B2 gene in five unrelated SLE patients by whole exome sequencing. They were characterized by autoimmunity, glomerulonephritis, leukopenia, and immune dysregulation. All variants were absent or ultrarare in population databases and predicted to be damaging by multiple in silico tools. Functional study showed that all the identified variants resulted in complete or partial enzymatic activity loss. Analyses of MAN2B2 knockout HEK293T cells, patient-derived induced pluripotent stem cells (iPSCs) and serum samples revealed defects in glycan degradation and N-glycosylation. The patients exhibited enhanced inflammatory signatures, especially the type I interferon and NF-κB pathways. Mechanically, MAN2B2 deficiency leads to dysregulation of unfolded protein response (UPR) upon endoplasmic reticulum stress, resulting in enhanced expression of inflammatory cytokines. Our findings broaden the genetic etiology spectrum of SLE and identify MAN2B2 as a pivotal regulator in maintaining immune homeostasis, paving the way for innovative diagnostic approaches and molecular pathway-specific therapeutic interventions.