{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T07:01:17Z","timestamp":1791529277494,"version":"4.3.4"},"reference-count":94,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2025,10,21]],"date-time":"2025-10-21T00:00:00Z","timestamp":1761004800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Amyotrophic lateral sclerosis (ALS) is a multisystem progressive neurodegenerative disease. A recent theory of ALS onsetting pathogenesis proposed that the initiating primary damage is an acquired irreversible intrafusal proprioceptive terminal PIEZO2 channelopathy with underlying genetic and environmental risk factors. This Piezo2 channelopathy may also disrupt the ultrafast proton-based oscillatory signaling to motor neurons through vesicular transporter 1 (VGLUT1) and to the hippocampus through VGLUT2. As a result, it may gradually degenerate motor neurons in which process Kv1.2 ion channels are gradually depleted. It also gradually depletes heat shock transcription factor-1 (HSF-1) in the hippocampus, hence negatively affecting adult hippocampal neurogenesis. Syndecans, especially syndecan-3 (SDC3) in the nervous system, may act as critical players in the maintenance of the crosstalk between Piezo ion channels. Hence, our goal was to reanalyze the potential pathogenic gene variants from the cohort of our previous ALS study with a special focus on the aforementioned genes. Reanalysis of data formerly acquired by whole-exome sequencing of 21 non-related adult ALS patients was carried out with a focus on 28 genes. Accordingly, we identified charge-altering variants of SDC3 in 13 patients out of 21 that may contribute to the impairment of the Piezo crosstalk, and the progressive loss of the proposed proton-based signaling to motor neurons and to the hippocampus. A variant of uncertain significance was identified in the KCNA2 gene that may facilitate the faster loss of Kv1.2 ion function on motor neurons when Piezo2 channelopathy prevails. Not to mention that one variant was identified in the potassium current rectifying ion channels encoding KCNK1 and KCNK16 genes that may also propel the ALS disease process and provide the autoimmune-like pathogenic background. Moreover, Piezo2 channelopathy likely promotes diminishing HSF1 function in the hippocampus in the presence of the identified HSF1 variant. The current findings may support the ALS onsetting acquired irreversible Piezo2 channelopathy-induced pathogenesis. However, the preliminary nature of these findings needs validation and further functional studies on cohorts with a larger sample size in the future.<\/jats:p>","DOI":"10.3390\/ijms262010218","type":"journal-article","created":{"date-parts":[[2025,10,21]],"date-time":"2025-10-21T13:42:03Z","timestamp":1761054123000},"page":"10218","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Genetic Variants in SDC3, KCNA2, KCNK1, KCNK16, and Heat Shock Transcription Factor-1 Genes: An Exploratory Analysis Supporting the Piezo2 Channelopathy Hypothesis in Amyotrophic Lateral Sclerosis Onset"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1267-1306","authenticated-orcid":false,"given":"Bal\u00e1zs","family":"Sonkodi","sequence":"first","affiliation":[{"name":"Department of Health Sciences and Sport Medicine, Hungarian University of Sports Science, 1124 Budapest, Hungary"},{"name":"Department of Sports Medicine, Semmelweis University, 1122 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6476-1181","authenticated-orcid":false,"given":"Zs\u00f3fia Fl\u00f3ra","family":"Nagy","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Albert Szent-Gy\u00f6rgyi Medical School, University of Szeged, 6720 Szeged, Hungary"},{"name":"Institute of Genomic Medicine and Rare Disorders, Semmelweis University, 1085 Budapest, Hungary"},{"name":"HUN-REN Functional Clinical Genetics Research Group, 6720 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4105-8458","authenticated-orcid":false,"given":"Anik\u00f3","family":"Keller-Pint\u00e9r","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Albert Szent-Gy\u00f6rgyi Medical School, University of Szeged, 6720 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5389-3266","authenticated-orcid":false,"given":"P\u00e9ter","family":"Kliv\u00e9nyi","sequence":"additional","affiliation":[{"name":"Department of Neurology, Albert Szent-Gy\u00f6rgyi Medical School, University of Szeged, 6725 Szeged, Hungary"},{"name":"HUN-REN-SZTE Neuroscience Research Group, Danube Neuroscience Research Laboratory, Hungarian Research Network, University of Szeged, 6725 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M\u00e1ria Judit","family":"Moln\u00e1r","sequence":"additional","affiliation":[{"name":"Institute of Genomic Medicine and Rare Disorders, Semmelweis University, 1085 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M\u00e1rta","family":"Sz\u00e9ll","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Albert Szent-Gy\u00f6rgyi Medical School, University of Szeged, 6720 Szeged, Hungary"},{"name":"HUN-REN Functional Clinical Genetics Research Group, 6720 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1367","DOI":"10.1001\/jamaneurol.2019.2044","article-title":"Lifetime Risk and Heritability of Amyotrophic Lateral Sclerosis","volume":"76","author":"Ryan","year":"2019","journal-title":"JAMA Neurol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1136\/jmedgenet-2020-106866","article-title":"Evidence for polygenic and oligogenic basis of Australian sporadic amyotrophic lateral sclerosis","volume":"58","author":"McCann","year":"2020","journal-title":"J. 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