{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,31]],"date-time":"2026-05-31T09:00:53Z","timestamp":1780218053242,"version":"3.54.0"},"reference-count":35,"publisher":"SAGE Publications","license":[{"start":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T00:00:00Z","timestamp":1777593600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T00:00:00Z","timestamp":1777593600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Ther Adv Respir Dis"],"published-print":{"date-parts":[[2026,5]]},"abstract":"<jats:sec>\n                    <jats:title>Background:<\/jats:title>\n                    <jats:p>\n                      Birt-Hogg-Dub\u00e9 (BHD) syndrome is an autosomal dominant disorder caused by folliculin (\n                      <jats:italic toggle=\"yes\">FLCN<\/jats:italic>\n                      ) gene mutations, with ethnically heterogeneous mutational spectra. Current management is primarily supportive and lacks curative therapies.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives:<\/jats:title>\n                    <jats:p>This study aimed to characterize the clinical features and genetic variants in two distinct Chinese families with BHD syndrome and to preliminarily explore the feasibility of an mRNA-based protein replacement approach.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Design:<\/jats:title>\n                    <jats:p>\n                      A family-based prospective cohort study was conducted to identify\n                      <jats:italic toggle=\"yes\">FLCN<\/jats:italic>\n                      mutations in two BHD families carrying rare\n                      <jats:italic toggle=\"yes\">FLCN<\/jats:italic>\n                      variants enrolled in 2023.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>\n                      Whole-exome sequencing (WES) identified candidate mutations in probands, which were validated by Sanger sequencing (p.W376R and p.Q44*). Structural\/functional impacts of p.W376R were analyzed via bioinformatics and qPCR. HEK293T cells were transfected with empty vector, wild-type\n                      <jats:italic toggle=\"yes\">FLCN<\/jats:italic>\n                      , or mutant plasmids (p.W376R and p.Q44*), followed by co-transfection with or without synthetic\n                      <jats:italic toggle=\"yes\">FLCN<\/jats:italic>\n                      mRNA.\n                      <jats:italic toggle=\"yes\">FLCN<\/jats:italic>\n                      expression and mTORC1 signaling were assessed.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>\n                      Affected members in both families predominantly presented with respiratory symptoms, lacking typical skin lesions and kidney tumors. WES identified the\n                      <jats:italic toggle=\"yes\">FLCN<\/jats:italic>\n                      variants p.W376R (previously classified as a Variant of Uncertain Significance, VUS) and a novel nonsense mutation p.Q44*. Genotype\u2013phenotype co-segregation was confirmed for p.W376R. In vitro analyses demonstrated that both mutations reduced FLCN protein expression, leading to mTORC1 hyperactivation. Exogenous\n                      <jats:italic toggle=\"yes\">FLCN<\/jats:italic>\n                      mRNA delivery rescued functional protein expression and reversed mTORC1 dysregulation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion:<\/jats:title>\n                    <jats:p>\n                      We provide co-segregation and functional evidence supporting the reclassification of the\n                      <jats:italic toggle=\"yes\">FLCN<\/jats:italic>\n                      p.W376R variant as pathogenic according to ACMG guidelines and report a novel pathogenic mutation, p.Q44*, expanding the known\n                      <jats:italic toggle=\"yes\">FLCN<\/jats:italic>\n                      mutational spectrum. Importantly,\n                      <jats:italic toggle=\"yes\">FLCN<\/jats:italic>\n                      mRNA supplementation restored FLCN expression in vitro, providing preliminary evidence for mRNA-based therapeutic strategies in BHD syndrome.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1177\/17534666261451630","type":"journal-article","created":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T11:29:33Z","timestamp":1779967773000},"update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":0,"title":["Novel\n                    <i>FLCN<\/i>\n                    mutations in Birt-Hogg-Dub\u00e9 patients and potential intervention of\n                    <i>FLCN<\/i>\n                    mRNA"],"prefix":"10.1177","volume":"20","author":[{"given":"Wenxue","family":"Bai","sequence":"first","affiliation":[{"name":"Department of Respiratory and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-0117-0394","authenticated-orcid":false,"given":"Mengyao","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Respiratory and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lijuan","family":"Hua","sequence":"additional","affiliation":[{"name":"Department of Respiratory and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuezhao","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Respiratory and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-2873-423X","authenticated-orcid":false,"given":"Lirong","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Respiratory and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3006-5564","authenticated-orcid":false,"given":"Bingyi","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Respiratory and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Respiratory and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Respiratory and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ni","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 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