Immunogenetic Studies in Patients With GAD-Positive Stiff-Person Syndrome Reveal Novel Lymphocytic Genes and...

The aim of this study was to identify genetic markers and immunologic characteristics of glutamic acid decarboxylase (GAD) antibody-positive patients with stiff-person syndrome (SPS).

We conducted systemic immunogenetic studies in 11 GAD-positive patients: 8 with sporadic SPS and 3 from a three-generation family with very high GAD-ab titers but diverse symptomatology (one with GAD-epilepsy and SPS and 2 only with diabetes), by performing complete immunologic profile and whole-exome sequencing analysis.

Two genes expressed in immune and neuronal tissues were identified: the ORAI1 that codes for a calcium release-activated channel protein with a role in the activation of T lymphocytes and the LILRA4 that encodes an IgG-like cell surface protein expressed in plasmacytoid dendritic cells. An important finding was the identification of 7 genetic polymorphisms in the novel Kallikrein 10 (KLK10) gene, shared by all 9 typical patients with SPS, as verified by Sanger sequencing, but not in the 2 GAD-positive family members with diabetes or the GAD-negative controls. To further verify these findings, Sanger sequencing was performed in 10 more patients with SPS and 15 autoimmune controls collectively confirmed that among a total of 39 tested samples, 95% of the 19 patients with SPS were homozygous or heterozygous for all 7 KLK10 variants while 90% of the 20 controls had the wild type or were heterozygous. KLK10 is a peptidase expressed in the choroid plexus epithelium and neuroendocrine organs and participates in the initiation of systemic inflammatory responses and immune-modulated disorders through proteolytic cascades.

KLK10 is a novel and potentially key genetic marker in patients with SPS that can contribute to disease pathogenesis by altering protease activity or the expression of neuron-to-immune cell signaling facilitating GAD autoimmunity. Along with the 2 newly identified immune-related genes, KLK10 is likely an interplay between genetic predisposition and immune dysregulation, necessitating the need to explore their significance as susceptibility disease factors and possibly as novel therapeutic targets.