PUBLICATION
Insights into KIF11 pathogenesis in Microcephaly-Lymphedema-Chorioretinopathy syndrome from a lymphatic perspective
- Authors
- Ogmen, K., Dobbins, S.E., Behncke, R.Y., Martinez-Corral, I., Brown, R.C., Meier, M., Ulferts, S., Hansmeier, N.R., Sackey, E., Alqahtani, A., Karapouliou, C., Grigoriadis, D., Del Rey Jimenez, J.C., Oberlin, M., Williams, D., Ekici, A., Karaer, K., Jeffery, S., Mortimer, P., Gordon, K., Okuda, K.S., Hogan, B.M., Mäkinen, T., Hägerling, R., Mansour, S., Martin-Almedina, S., Ostergaard, P.
- ID
- ZDB-PUB-251223-4
- Date
- 2025
- Source
- JCI insight : (Journal)
- Registered Authors
- Brown, Ryan, Hogan, Ben M.
- Keywords
- Cardiovascular disease, Clinical Research, Genetics, Molecular genetics, Vascular biology
- MeSH Terms
-
- Animals
- Endothelial Cells/metabolism
- Female
- Homeodomain Proteins/genetics
- Homeodomain Proteins/metabolism
- Humans
- Kinesins*/genetics
- Kinesins*/metabolism
- Lymphangiogenesis/genetics
- Lymphedema*/genetics
- Lymphedema*/pathology
- Male
- Mice
- Microcephaly*/genetics
- Microcephaly*/pathology
- Prospero-Related Homeobox 1 Protein
- Retinal Diseases*/genetics
- Tumor Suppressor Proteins/metabolism
- Vascular Endothelial Growth Factor C/metabolism
- Vascular Endothelial Growth Factor Receptor-3/genetics
- Vascular Endothelial Growth Factor Receptor-3/metabolism
- Zebrafish
- PubMed
- 41427784 Full text @ JCI Insight
Citation
Ogmen, K., Dobbins, S.E., Behncke, R.Y., Martinez-Corral, I., Brown, R.C., Meier, M., Ulferts, S., Hansmeier, N.R., Sackey, E., Alqahtani, A., Karapouliou, C., Grigoriadis, D., Del Rey Jimenez, J.C., Oberlin, M., Williams, D., Ekici, A., Karaer, K., Jeffery, S., Mortimer, P., Gordon, K., Okuda, K.S., Hogan, B.M., Mäkinen, T., Hägerling, R., Mansour, S., Martin-Almedina, S., Ostergaard, P. (2025) Insights into KIF11 pathogenesis in Microcephaly-Lymphedema-Chorioretinopathy syndrome from a lymphatic perspective. JCI insight. :.
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 MLC patients 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, scRNA-seq identified kif11 specifically expressed in endothelial precursors. In human lymphatic endothelial cells (LECs), 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 a link between KIF11 and drivers of lymphangiogenesis and lymphatic identity.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping