{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T16:17:32Z","timestamp":1792685852394,"version":"4.5.0"},"reference-count":38,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"9","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JASN"],"published-print":{"date-parts":[[2016,9]]},"abstract":"<jats:p>\n                    FSGS is a CKD with heavy proteinuria that eventually progresses to ESRD. Hereditary forms of FSGS have been linked to mutations in the\n                    <jats:italic toggle=\"yes\">transient receptor potential cation channel, subfamily C, member 6<\/jats:italic>\n                    (\n                    <jats:italic toggle=\"yes\">TRPC6<\/jats:italic>\n                    ) gene encoding a nonselective cation channel. Most of these\n                    <jats:italic toggle=\"yes\">TRPC6<\/jats:italic>\n                    mutations cause a gain-of-function phenotype, leading to calcium\u2013triggered podocyte cell death, but the underlying molecular mechanisms are unclear. We studied the molecular effect of disease-related mutations using tridimensional\n                    <jats:italic toggle=\"yes\">in silico<\/jats:italic>\n                    modeling of tetrameric TRPC6. Our results indicated that G757 is localized in a domain forming a TRPC6-TRPC6 interface and predicted that the amino acid exchange G757D causes local steric hindrance and disruption of the channel complex. Notably, functional characterization of model interface domain mutants suggested a loss-of-function phenotype. We then characterized 19 human FSGS\u2013related TRPC6 mutations, the majority of which caused gain-of-function mutations. However, five mutations (N125S, L395A, G757D, L780P, and R895L) caused a loss-of-function phenotype. Coexpression of wild-type TRPC6 and TRPC6 G757D, mimicking heterozygosity observed in patients, revealed a dominant negative effect of TRPC6 G757D. Our comprehensive analysis of human disease\u2013causing TRPC6 mutations reveals loss of TRPC6 function as an additional concept of hereditary FSGS and provides molecular insights into the mechanism responsible for the loss-of-function phenotype of TRPC6 G757D in humans.\n                  <\/jats:p>","DOI":"10.1681\/asn.2015030318","type":"journal-article","created":{"date-parts":[[2016,2,18]],"date-time":"2016-02-18T23:26:07Z","timestamp":1455837967000},"page":"2771-2783","source":"Crossref","is-referenced-by-count":113,"title":["TRPC6 G757D Loss-of-Function Mutation Associates with FSGS"],"prefix":"10.1681","volume":"27","author":[{"given":"Marc","family":"Riehle","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Experimental Therapy, Institute of Experimental and Clinical Pharmacology and Toxicology, Eberhard Karls University Hospitals and Clinics and Interfaculty Center of Pharmacogenomics and Drug Research, University of T\u00fcbingen, T\u00fcbingen, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anja K.","family":"B\u00fcscher","sequence":"additional","affiliation":[{"name":"Pediatric Nephrology, Pediatrics II, University of Duisburg-Essen, Essen, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bj\u00f6rn-Oliver","family":"Gohlke","sequence":"additional","affiliation":[{"name":"German Cancer Consortium, Heidelberg, Germany;"},{"name":"Charit\u00e9 University Medicine Berlin, Structural Bioinformatics Group, Institute of Physiology and Experimental Clinical Research Center, Berlin, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario","family":"Ka\u00dfmann","sequence":"additional","affiliation":[{"name":"Nephrology\/Intensive Care, Experimental and Clinical Research Center and Max Delbr\u00fcck Center for Molecular Medicine, Charit\u00e9 University Medicine Berlin, Berlin, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Kolatsi-Joannou","sequence":"additional","affiliation":[{"name":"Nephro-Urology Unit, University College London Institute of Child Health, London, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan H.","family":"Br\u00e4sen","sequence":"additional","affiliation":[{"name":"Institute of Pathology, University Hospital of Hannover, Hannover, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mato","family":"Nagel","sequence":"additional","affiliation":[{"name":"Center of Nephrology and Metabolism, Weisswasser, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan U.","family":"Becker","sequence":"additional","affiliation":[{"name":"Institute of Pathology, University Hospital of Cologne, Cologne, Germany; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Winyard","sequence":"additional","affiliation":[{"name":"Nephro-Urology Unit, University College London Institute of Child Health, London, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter F.","family":"Hoyer","sequence":"additional","affiliation":[{"name":"Pediatric Nephrology, Pediatrics II, University of Duisburg-Essen, Essen, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Preissner","sequence":"additional","affiliation":[{"name":"German Cancer Consortium, Heidelberg, Germany;"},{"name":"Charit\u00e9 University Medicine Berlin, Structural Bioinformatics Group, Institute of Physiology and Experimental Clinical Research Center, Berlin, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dietmar","family":"Krautwurst","sequence":"additional","affiliation":[{"name":"Deutsche Forschungsanstalt f\u00fcr Lebensmittelchemie, Molekulare Zellphysiologie und Chemorezeption, Freising, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maik","family":"Gollasch","sequence":"additional","affiliation":[{"name":"Nephrology\/Intensive Care, Experimental and Clinical Research Center and Max Delbr\u00fcck Center for Molecular Medicine, Charit\u00e9 University Medicine Berlin, Berlin, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefanie","family":"Weber","sequence":"additional","affiliation":[{"name":"Pediatric Nephrology, Pediatrics II, University of Duisburg-Essen, Essen, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Harteneck","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Experimental Therapy, Institute of Experimental and Clinical Pharmacology and Toxicology, Eberhard Karls University Hospitals and Clinics and Interfaculty Center of Pharmacogenomics and Drug Research, University of T\u00fcbingen, T\u00fcbingen, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2016,2,18]]},"reference":[{"key":"B1-20231016","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1038\/nrneph.2014.216","article-title":"Causes and pathogenesis of focal segmental glomerulosclerosis.","volume":"11","author":"Fogo","year":"2015","journal-title":"Nat Rev Nephrol"},{"key":"B2-20231016","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1016\/S0272-6386(97)90485-6","article-title":"Changing etiologies of unexplained adult nephrotic syndrome: A comparison of renal biopsy findings from 1976-1979 and 1995-1997.","volume":"30","author":"Haas","year":"1997","journal-title":"Am J Kidney Dis"},{"key":"B3-20231016","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1016\/0272-6386(95)90120-5","article-title":"Focal segmental glomerular sclerosis in adults: Presentation, course, and response to 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