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We identified 4 individuals with CCLA, lymphedema, and microcystic lymphatic malformation due to pathogenic, mosaic variants in\n                    <jats:italic>KRAS<\/jats:italic>\n                    . To determine the functional impact of these variants and identify a targeted therapy for these individuals, we used primary human dermal lymphatic endothelial cells (HDLECs) and zebrafish larvae to model the lymphatic dysplasia. Expression of the p.Gly12Asp and p.Gly13Asp variants in HDLECs in a 2\u2011dimensional (2D) model and 3D organoid model led to increased ERK phosphorylation, demonstrating these variants activate the RAS\/MAPK pathway. Expression of activating\n                    <jats:italic>KRAS<\/jats:italic>\n                    variants in the venous and lymphatic endothelium in zebrafish resulted in lymphatic dysplasia and edema similar to the individuals in the study. Treatment with MEK inhibition significantly reduced the phenotypes in both the organoid and the zebrafish model systems. In conclusion, we present the molecular characterization of the observed lymphatic anomalies due to pathogenic, somatic, activating\n                    <jats:italic>KRAS<\/jats:italic>\n                    variants in humans. Our preclinical studies suggest that MEK inhibition should be studied in future clinical trials for CCLA due to activating\n                    <jats:italic>KRAS<\/jats:italic>\n                    pathogenic variants.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.155888","type":"journal-article","created":{"date-parts":[[2023,5,7]],"date-time":"2023-05-07T14:01:06Z","timestamp":1683468066000},"source":"Crossref","is-referenced-by-count":44,"title":["Lymphatic disorders caused by mosaic, activating KRAS variants respond to MEK inhibition"],"prefix":"10.1172","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3480-8123","authenticated-orcid":true,"given":"Sarah E.","family":"Sheppard","sequence":"first","affiliation":[{"name":"Center for Applied Genomics,"},{"name":"Division of Human Genetics, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9173-6862","authenticated-orcid":true,"given":"Michael E.","family":"March","sequence":"additional","affiliation":[{"name":"Center for Applied Genomics,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph","family":"Seiler","sequence":"additional","affiliation":[{"name":"Zebrafish Core, Children\u2019s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leticia S.","family":"Matsuoka","sequence":"additional","affiliation":[{"name":"Center for Applied Genomics,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophia E.","family":"Kim","sequence":"additional","affiliation":[{"name":"Center for Applied Genomics,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charlly","family":"Kao","sequence":"additional","affiliation":[{"name":"Center for Applied Genomics,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9273-1817","authenticated-orcid":true,"given":"Adam I.","family":"Rubin","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Perelman School of Medicine at the University of Pennsylvania, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7831-6935","authenticated-orcid":true,"given":"Mark R.","family":"Battig","sequence":"additional","affiliation":[{"name":"Center for Applied Genomics,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nahla","family":"Khalek","sequence":"additional","affiliation":[{"name":"Richard D. 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