{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T17:37:05Z","timestamp":1785173825576,"version":"3.55.0"},"reference-count":28,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2026,1,8]],"date-time":"2026-01-08T00:00:00Z","timestamp":1767830400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006769","name":"Russian Science Foundation","doi-asserted-by":"publisher","award":["24-24-00410"],"award-info":[{"award-number":["24-24-00410"]}],"id":[{"id":"10.13039\/501100006769","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["CIMB"],"abstract":"<jats:p>Vascular endothelial growth factor receptor 3 (VEGFR3) assumes a pivotal role in regulating the development and maintaining the structural integrity of the lymphatic system. Decreased activity of VEGFR3 can precipitate aplasia or hypoplasia of lymphatic system components, culminating in primary lymphedema. To date, numerous genetic variants have been identified within the FLT4 gene, which encodes VEGFR3; however, the majority of these remain uncharacterised and are classified as \u2018variants of uncertain significance\u2019. In preceding investigations involving FLT4 sequence analysis conducted on individuals presenting with primary lymphedema, we identified several rare genetic variants that possess the potential to modulate the functional activity of VEGFR3, including the heterozygous variant c.3175G&gt;C (p.A1059P). Preliminary assessments encompassing clinical characteristics, family history, and predictive computational algorithms indicated that this variant was likely pathogenic. Consequently, this study presents the results of functional evaluation of the mutant VEGFR3 activity in cell models overexpressing the FLT4 variant c.3175G&gt;C. VEGFC-dependent VEGFR3 phosphorylation and FLT4 expression were reduced in cells with c.3175G&gt;C FLT4 variant compared to wild-type, confirming the pathogenic role of c.3175G&gt;C in primary lymphedema.<\/jats:p>","DOI":"10.3390\/cimb48010068","type":"journal-article","created":{"date-parts":[[2026,1,8]],"date-time":"2026-01-08T10:10:50Z","timestamp":1767867050000},"page":"68","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Decreased Kinase Activity of the VEGFR3 Variant c.3175G&gt;C Associated with Primary Lymphedema"],"prefix":"10.3390","volume":"48","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1853-8365","authenticated-orcid":false,"given":"Yuliya V.","family":"Filina","sequence":"first","affiliation":[{"name":"Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, Kazan 420008, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2473-5514","authenticated-orcid":false,"given":"Maria A.","family":"Zolotykh","sequence":"additional","affiliation":[{"name":"Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, Kazan 420008, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6686-1968","authenticated-orcid":false,"given":"Regina R.","family":"Miftakhova","sequence":"additional","affiliation":[{"name":"Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, Kazan 420008, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,8]]},"reference":[{"key":"ref_1","first-page":"309","article-title":"Milroy\u2019s primary congenital lymphedema in a male infant and review of the literature","volume":"24","author":"Vrettou","year":"2010","journal-title":"In Vivo"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1002\/humu.22223","article-title":"FLT4\/VEGFR3 and Milroy disease: Novel mutations, a review of published variants and database update","volume":"34","author":"Gordon","year":"2013","journal-title":"Hum. Mutat."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"943","DOI":"10.1016\/j.ajhg.2010.04.010","article-title":"GJC2 missense mutations cause human lymphedema","volume":"86","author":"Ferrell","year":"2010","journal-title":"Am. J. Hum. Genet."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1159\/000354097","article-title":"Mutations in the VEGFR3 signaling pathway explain 36% of familial lymphedema","volume":"4","author":"Mendola","year":"2013","journal-title":"Mol. Syndromol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"552","DOI":"10.7861\/clinmedicine.17-6-552","article-title":"An approach to familial lymphoedema","volume":"17","author":"Jones","year":"2017","journal-title":"Clin. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"898","DOI":"10.1172\/JCI71614","article-title":"Genetics of lymphatic anomalies","volume":"124","author":"Brouillard","year":"2014","journal-title":"J. Clin. Investig."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"3566","DOI":"10.1073\/pnas.92.8.3566","article-title":"Expression of the fms-like tyrosine kinase 4 gene becomes restricted to lymphatic endothelium during development","volume":"92","author":"Kaipainen","year":"1995","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"946","DOI":"10.1126\/science.282.5390.946","article-title":"Cardiovascular Failure in Mouse Embryos Deficient in VEGF Receptor-3","volume":"282","author":"Dumont","year":"1998","journal-title":"Science"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1028","DOI":"10.1096\/fsb2fj000383com","article-title":"VEGFR3 gene structure, regulatory region, and sequence polymorphisms","volume":"15","author":"Iljin","year":"2001","journal-title":"FASEB J."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1136\/jmg.2004.024802","article-title":"Milroy disease and the VEGFR-3 mutation phenotype","volume":"42","author":"Brice","year":"2005","journal-title":"J. Med. Genet."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"3162","DOI":"10.1177\/0300060518773264","article-title":"A novel mutation in the conserved sequence of vascular endothelial growth factor receptor 3 leads to primary lymphoedema","volume":"46","author":"Dai","year":"2018","journal-title":"J. Int. Med. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1001","DOI":"10.1038\/s41436-018-0260-9","article-title":"Haploinsufficiency of vascular endothelial growth factor related signaling genes is associated with tetralogy of Fallot","volume":"21","author":"Reuter","year":"2019","journal-title":"Genet. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1111\/cge.14671","article-title":"Identification of a Novel FLT4 c.3028A>C Variant Associated with Milroy Disease","volume":"107","author":"Feiskhanov","year":"2025","journal-title":"Clin. Genet."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1016\/j.ccell.2018.01.021","article-title":"Systematic Functional Annotation of Somatic Mutations in Cancer","volume":"33","author":"Ng","year":"2018","journal-title":"Cancer Cell"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1002\/0471142301.ns0421s37","article-title":"Production and titration of lentiviral vectors","volume":"37","author":"Salmon","year":"2006","journal-title":"Curr. Protoc. Neurosci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1261\/rna.2192803","article-title":"Lentivirus-delivered stable gene silencing by RNAi in primary cells","volume":"9","author":"Stewart","year":"2003","journal-title":"RNA"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"D265","DOI":"10.1093\/nar\/gkz991","article-title":"CDD\/SPARCLE: The conserved domain database in 2020","volume":"48","author":"Lu","year":"2020","journal-title":"Nucleic Acids Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1912","DOI":"10.1126\/science.1075762","article-title":"The protein kinase complement of the human genome","volume":"298","author":"Manning","year":"2002","journal-title":"Science"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Pechmann, S., and Frydman, J. (2014). Interplay between chaperones and protein disorder promotes the evolution of protein networks. PLoS Comput. Biol., 10.","DOI":"10.1371\/journal.pcbi.1003674"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1089\/gtmb.2010.0036","article-title":"Using SIFT and PolyPhen to predict loss-of-function and gain-of-function mutations","volume":"14","author":"Flanagan","year":"2010","journal-title":"Genet. Test. Mol. Biomark."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Liu, N., and Gao, M. (2021). FLT4 Mutations Are Associated with Segmental Lymphatic Dysfunction and Initial Lymphatic Aplasia in Patients with Milroy Disease. Genes, 12.","DOI":"10.3390\/genes12101611"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1038\/ni1013","article-title":"Vascular endothelial growth factor C is required for sprouting of the first lymphatic vessels from embryonic veins","volume":"5","author":"Karkkainen","year":"2004","journal-title":"Nat. Immunol."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Kuonqui, K.G., Campbell, A.C., Pollack, B.L., Shin, J., Sarker, A., Brown, S., Park, H.J., Mehrara, B.J., and Kataru, R.P. (2025). Regulation of VEGFR3 signaling in lymphatic endothelial cells. Front. Cell Dev. Biol., 13.","DOI":"10.3389\/fcell.2025.1527971"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1038\/75997","article-title":"Missense mutations interfere with VEGFR-3 signalling in primary lymphoedema","volume":"25","author":"Karkkainen","year":"2000","journal-title":"Nat. Genet."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"304","DOI":"10.3390\/cells3020304","article-title":"Mechanisms of activation of receptor tyrosine kinases: Monomers or dimers","volume":"3","author":"Maruyama","year":"2014","journal-title":"Cells"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1038\/jid.2008.246","article-title":"Functional analysis of FLT4 mutations associated with Nonne-Milroy lymphedema","volume":"129","author":"Verstraeten","year":"2009","journal-title":"J. Investig. Dermatol."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Sudhesh Dev, S., Zainal Abidin, S.A., Farghadani, R., Othman, I., and Naidu, R. (2021). Receptor Tyrosine Kinases and Their Signaling Pathways as Therapeutic Targets of Curcumin in Cancer. Front. Pharmacol., 12.","DOI":"10.3389\/fphar.2021.772510"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."}],"container-title":["Current Issues in Molecular Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1467-3045\/48\/1\/68\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,8]],"date-time":"2026-01-08T10:40:25Z","timestamp":1767868825000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1467-3045\/48\/1\/68"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,8]]},"references-count":28,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,1]]}},"alternative-id":["cimb48010068"],"URL":"https:\/\/doi.org\/10.3390\/cimb48010068","relation":{},"ISSN":["1467-3045"],"issn-type":[{"value":"1467-3045","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,8]]}}}