Insights into KIF11 pathogenesis in microcephaly-lymphedema-chorioretinopathy syndrome from a lymphatic perspective

Ogmen, K; Brown, RC; Dobbins, SE; Behncke, RY; Martinez-Corral, I; Meier, M; Ulferts, S; Hansmeier, NR; Sackey, E; Alqahtani, A; Karapouliou, C; Grigoriadis, D; Del Rey Jimenez, JC; Oberlin, M; Williams, D; Ekici, A; Karaer, K; Jeffery, S; Mortimer, P; Gordon, K; Okuda, KS; Hogan, BM; M&#228;kinen, T; H&#228;gerling, R; Mansour, S; Martin-Almedina, S; Ostergaard, P

Author(s): Ogmen, K; Brown, RC; Dobbins, SE; Behncke, RY; Martinez-Corral, I; Meier, M; Ulferts, S; Hansmeier, NR; Sackey, E; Alqahtani, A; Karapouliou, C; Grigoriadis, D; Del Rey Jimenez, JC; Oberlin, M; Williams, D; Ekici, A; Karaer, K; Jeffery, S; Mortimer, P; Gordon, K; Okuda, KS; Hogan, BM; Mäkinen, T; Hägerling, R; Mansour, S; Martin-Almedina, S; Ostergaard, P;
Details: Publication Year 2026-02-09,Volume 11,Issue #3,Page e177656
Journal Title: JCI Insight
Publication Type: Research article
Abstract: Pathogenic variants in kinesin KIF11 underlie microcephaly-lymphedema-chorioretinopathy (MLC) syndrome. Although well known for regulating spindle dynamics ensuring successful cell division, the association of KIF11 (encoding EG5) with development of the lymphatic system and how KIF11 pathogenic variants lead to lymphatic dysfunction and lymphedema remain unknown. Using patient-derived lymphoblastoid cells, we demonstrated that patients with MLC carrying pathogenic stop-gain variants in KIF11 have reduced mRNA and protein levels. Lymphoscintigraphy showed reduced tracer absorption, and intestinal lymphangiectasia was detected in one patient, pointing to impairment of lymphatic function caused by KIF11 haploinsufficiency. We revealed that KIF11 is expressed in early human and mouse development with the lymphatic markers VEGFR3, podoplanin, and PROX1. In zebrafish, single-cell RNA-Seq identified kif11 specifically expressed in endothelial precursors. In human lymphatic endothelial cells, EG5 inhibition with ispinesib reduced VEGFC-driven AKT phosphorylation, migration, and spheroid sprouting. KIF11 knockdown reduced PROX1 and VEGFR3 expression, providing for the first time to our knowledge a link between KIF11 and drivers of lymphangiogenesis and lymphatic identity.
Keywords: Humans; *Kinesins/genetics/metabolism; *Microcephaly/genetics/pathology; *Lymphedema/genetics/pathology; Animals; Mice; Zebrafish; Prospero-Related Homeobox 1 Protein; Female; Male; Vascular Endothelial Growth Factor Receptor-3/metabolism/genetics; Tumor Suppressor Proteins/metabolism; *Retinal Diseases/genetics; Endothelial Cells/metabolism; Vascular Endothelial Growth Factor C/metabolism; Lymphangiogenesis/genetics; Homeodomain Proteins/metabolism/genetics; Cardiovascular disease; Clinical Research; Genetics; Molecular genetics; Vascular biology
Department(s): Laboratory Research
Publisher's Version: https://doi.org/10.1172/jci.insight.177656
Open Access at Publisher's Site: https://doi.org/10.1172/jci.insight.177656
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2026-01-23 11:58:24

Last Modified: 2026-02-26 02:13:20