SIAE Rare Variants in Juvenile Idiopathic Arthritis and Primary Antibody Deficiencies

Abstract

Sialic acid acetylesterase (SIAE) deficiency was suggested to lower the levels of ligands for sialic acid-binding immunoglobulin-like receptors, decreasing the threshold for B-cell activation. In humans, studies of rare heterozygous loss-of-function mutations in SIAE gene in common autoimmune diseases, including juvenile idiopathic arthritis (JIA), yielded inconsistent results. Considering the distinct pathogenesis of the two main subtypes of JIA, autoinflammatory systemic (sJIA) and autoimmune oligo/polyarticular (aJIA), and a predisposition to autoimmunity displayed by patients and families with primary antibody deficiencies (PADs), the aim of our study was to analyze whether SIAE rare variants are associated with both the phenotype of JIA and the autoimmunity risk in families with PADs. A cohort of 69 patients with JIA, 117 healthy children, 54 patients, and family members with PADs were enrolled in the study. Three novel SIAE variants (p.Q343P, p.Y495X, and c.1320+33T>C) were found only in patients with aJIA but interestingly also in their healthy relatives without autoimmunity, while none of PAD patients or their relatives carried SIAE defects. Our results show that SIAE rare variants are not causative of autoimmunity as single defects.

Circular RNAs Hsa_circ_0002715 and Hsa_circ_0035197 in Peripheral Blood Are Novel Potential Biomarkers for New-Onset Rheumatoid Arthritis

“…SIAE is an enzyme which catalyzes the removal of 9-O-acetylation modifications from sialic acids. Previous studies have demonstrated that some mutations in this gene are associated with susceptibility to common autoimmune disease, such as juvenile idiopathic arthritis [28]. However, Zhang et al [29] found no association between SIAE gene mutation and RA in a Han Chinese population.…”

Sialic acid O-acetylation: From biosynthesis to roles in health and disease

“…This notion was initially supported by studies with Siae knock-out mice that showed enhanced O-acetylation of α2-6-linked Sias on N-glycans and defective B cell tolerance formation (138). However, recently it was discovered that the B cell phenotype in the mice was related to unintended disruption of Dock2, but not Siae (139), and results from genetic association studies investigating the link between SIAE polymorphisms and autoimmunity are conflicting (140)(141)(142)(143). While it is generally accepted that O-acetylation masks sialoglycan ligands for Siglec-2, Siglec2 knock-out alone in mice was not sufficient to induce B cell abnormalities, but required additional knock-out of Siglecg, probably due to redundant functions of these Siglecs (144).…”