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Pathogenic variants in various genes have been identified in about 30% of PL cases. By screening of a cohort of 755 individuals with PL, we identified two\n                    <jats:italic>TIE1<\/jats:italic>\n                    (tyrosine kinase with immunoglobulin- and epidermal growth factor\u2013like domains 1) missense variants and one truncating variant, all predicted to be pathogenic by bioinformatic algorithms. The TIE1 receptor, in complex with TIE2, binds angiopoietins to regulate the formation and remodeling of blood and lymphatic vessels. The premature stop codon mutant encoded an inactive truncated extracellular TIE1 fragment with decreased mRNA stability, and the amino acid substitutions led to decreased TIE1 signaling activity. By reproducing the two missense variants in mouse\n                    <jats:italic>Tie1<\/jats:italic>\n                    via CRISPR\/Cas9, we showed that both cause edema and are lethal in homozygous mice. Thus, our results indicate that TIE1 loss-of-function variants can cause lymphatic dysfunction in patients. Together with our earlier demonstration that ANGPT2 loss-of-function mutations can also cause PL, our results emphasize the important role of the ANGPT2\/TIE1 pathway in lymphatic function.\n                  <\/jats:p>","DOI":"10.1172\/jci173586","type":"journal-article","created":{"date-parts":[[2024,5,31]],"date-time":"2024-05-31T13:59:11Z","timestamp":1717163951000},"source":"Crossref","is-referenced-by-count":25,"title":["Loss-of-function mutations of the TIE1 receptor tyrosine kinase cause late-onset primary lymphedema"],"prefix":"10.1172","volume":"134","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9548-8229","authenticated-orcid":true,"given":"Pascal","family":"Brouillard","sequence":"first","affiliation":[{"name":"Human Molecular Genetics, de Duve Institute, University of Louvain, Brussels, Belgium."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aino","family":"Murtom\u00e4ki","sequence":"additional","affiliation":[{"name":"Wihuri Research Institute, 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