Document Type
Article
Publication Date
3-1-2025
Abstract
BACKGROUND AND OBJECTIVES: 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).
METHODS: 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.
RESULTS: 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.
DISCUSSION: 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.
Recommended Citation
Tsiortou, Popianna; Alexopoulos, Harry; Kyriakidis, Konstantinos; Kosmidis, Michalis; Barba, Chrysanthi; Akrivou, Sofia; Michalopoulos, Ioannis; Politis, Panagiotis; and Dalakas, Marinos, "Immunogenetic Studies in Patients with GAD-Positive Stiff-Person Syndrome Reveal Novel Lymphocytic Genes and KLK10 -Gene Variants" (2025). Department of Neurology Faculty Papers. Paper 356.
https://jdc.jefferson.edu/neurologyfp/356
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.
PubMed ID
39933127
Language
English
Included in
Biological Factors Commons, Genetic Phenomena Commons, Immune System Diseases Commons, Nervous System Diseases Commons, Neurology Commons
Comments
This article is the author's final published version in Neurology: Neuroimmunology and NeuroInflammation, Volume 12, Issue 2, February 2025, Article number e200373.
The published version is available at https://doi.org/10.1212/NXI.0000000000200373.
Copyright © 2025 The Author(s)