{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T18:54:55Z","timestamp":1793040895133,"version":"4.5.0"},"reference-count":38,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2022,7,22]],"date-time":"2022-07-22T00:00:00Z","timestamp":1658448000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"DFG","doi-asserted-by":"publisher","award":["DE1482-9\/2"],"award-info":[{"award-number":["DE1482-9\/2"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The voltage-dependent L-type calcium channel isoform CaV1.2 is critically involved in many physiological processes, e.g., in cardiac action potential formation, electromechanical coupling and regulation of insulin secretion by beta cells. Gain-of-function mutations in the calcium voltage-gated channel subunit alpha 1 C (CACNA1C) gene, encoding the CaV1.2 \u03b11-subunit, cause Timothy syndrome (TS), a multisystemic disorder that includes autism spectrum disorders and long QT (LQT) syndrome. Strikingly, TS patients frequently suffer from hypoglycemia of yet unproven origin. Using next-generation sequencing, we identified a novel heterozygous CACNA1C mutation in a patient with congenital hyperinsulinism (CHI) and associated hypoglycemic episodes. We characterized the electrophysiological phenotype of the mutated channel using voltage-clamp recordings and in silico action potential modeling experiments. The identified CaV1.2L566P mutation causes a mixed electrophysiological phenotype of gain- and loss-of-function effects. In silico action potential modeling supports that this mixed electrophysiological phenotype leads to a tissue-specific impact on beta cells compared to cardiomyocytes. Thus, CACNA1C variants may be associated with non-syndromic hyperinsulinemic hypoglycemia without long-QT syndrome, explained by very specific electrophysiological properties of the mutated channel. We discuss different biochemical characteristics and clinical impacts of hypoglycemia in the context of CACNA1C variants and show that these may be associated with significant morbidity for Timothy Syndrome patients. Our findings underline that the potential of hypoglycemia warrants careful attention in patients with CACNA1C variants, and such variants should be included in the differential diagnosis of non-syndromic congenital hyperinsulinism.<\/jats:p>","DOI":"10.3390\/ijms23158097","type":"journal-article","created":{"date-parts":[[2022,7,22]],"date-time":"2022-07-22T12:53:45Z","timestamp":1658494425000},"page":"8097","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Hyperinsulinemic Hypoglycemia Associated with a CaV1.2 Variant with Mixed Gain- and Loss-of-Function Effects"],"prefix":"10.3390","volume":"23","author":[{"given":"Sebastian","family":"Kummer","sequence":"first","affiliation":[{"name":"Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children\u2019s Hospital, 40225 Duesseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanne","family":"Rinn\u00e9","sequence":"additional","affiliation":[{"name":"Institute of Physiology and Pathophysiology, Vegetative Physiology, University of Marburg, 35043 Marburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gunnar","family":"Seemann","sequence":"additional","affiliation":[{"name":"Institute for Experimental Cardiovascular Medicine, University Heart Center Freiburg\u2014Bad Krozingen, Medical Center\u2014University of Freiburg, 79085 Freiburg im Breisgau, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadine","family":"Bachmann","sequence":"additional","affiliation":[{"name":"Medizinische Genetik Mainz, Limbach Genetics, 55128 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine","family":"Timothy","sequence":"additional","affiliation":[{"name":"Children\u2019s Hospital Boston, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul S.","family":"Thornton","sequence":"additional","affiliation":[{"name":"Division of Endocrinology and Diabetes, Cook Children\u2019s Medical Center, Fort Worth, TX 76104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank","family":"Pillekamp","sequence":"additional","affiliation":[{"name":"Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children\u2019s Hospital, 40225 Duesseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8460-3738","authenticated-orcid":false,"given":"Ertan","family":"Mayatepek","sequence":"additional","affiliation":[{"name":"Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children\u2019s Hospital, 40225 Duesseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carsten","family":"Bergmann","sequence":"additional","affiliation":[{"name":"Medizinische Genetik Mainz, Limbach Genetics, 55128 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Meissner","sequence":"additional","affiliation":[{"name":"Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children\u2019s Hospital, 40225 Duesseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9433-687X","authenticated-orcid":false,"given":"Niels","family":"Decher","sequence":"additional","affiliation":[{"name":"Institute of Physiology and Pathophysiology, Vegetative Physiology, University of Marburg, 35043 Marburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,7,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.cell.2004.09.011","article-title":"CaV1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism","volume":"119","author":"Splawski","year":"2004","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1210\/er.2005-0888","article-title":"The role of voltage-gated calcium channels in pancreatic beta-cell physiology and pathophysiology","volume":"27","author":"Yang","year":"2006","journal-title":"Endocr. 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