Insights into KIF11 pathogenesis in microcephaly-lymphedema-chorioretinopathy syndrome from a lymphatic perspective
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.
Authors
- Dionysios Grigoriadis (ORCID: https://orcid.org/0000-0002-9502-6590)
- Peter G. Mortimer (ORCID: https://orcid.org/0000-0003-2900-2336)
- Sascha Ulferts (ORCID: https://orcid.org/0009-0006-3861-4966)
- René Hägerling (ORCID: https://orcid.org/0000-0002-6830-2043)
- Ahlam Alqahtani (ORCID: https://orcid.org/0000-0003-1145-8474)
- Christina Karapouliou (ORCID: https://orcid.org/0000-0002-9942-2718)
- Kazuhide S. Okuda (ORCID: https://orcid.org/0000-0002-8060-0377)
- Steve Jeffery
- Ege Sackey (ORCID: https://orcid.org/0000-0001-5477-0965)
- Nils Rouven Hansmeier (ORCID: https://orcid.org/0000-0001-7024-5351)
- Taija Mäkinen (ORCID: https://orcid.org/0000-0002-9338-1257)
- Kazim Ogmen (ORCID: https://orcid.org/0000-0003-2792-3158)
- Kristiana Gordon (ORCID: https://orcid.org/0000-0002-7840-5644)
- Kadri Karaer (ORCID: https://orcid.org/0000-0003-1415-9103)
- Benjamin M. Hogan (ORCID: https://orcid.org/0000-0002-0651-7065)
- Rose Yinghan Behncke (ORCID: https://orcid.org/0009-0005-8503-3411)
- Juan Carlos Del Rey Jimenez
- Michelle Meier (ORCID: https://orcid.org/0009-0005-5595-3882)
- Sahar Mansour
- Ryan C.S. Brown
- Pia Ostergaard
- Silvia Martin-Almedina
- Ines Martinez-Corral
- Denise Williams
- Michael Oberlin
- Sara E. Dobbins
- Arzu Ekici
Institutions
- Uppsala University (SE)
- University of Helsinki (FI)
- European Centre for Minority Issues (DE)
- St George's, University of London (GB)
- Peter MacCallum Cancer Centre (AU)
- St George’s University Hospitals NHS Foundation Trust (GB)
- Government of the United Kingdom (GB)
- Wihuri Research Institute (FI)
- Sağlık Bilimleri Üniversitesi (TR)
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin (DE)
- Max Planck Institute for Molecular Genetics (DE)
- S.B.Ü. Bursa Yüksek İhtisas Eğitim ve Araştırma Hastanesi (TR)
- Pamukkale University (TR)
- Charité - Universitätsmedizin Berlin (DE)
- Newcastle University (GB)
Publication Details
- Journal
- JCI Insight
- Published
- 2025-12-18
- DOI
- https://doi.org/10.1172/jci.insight.177656
- Primary Topic
- Lymphatic System and Diseases
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- British Heart Foundation
- Rosetrees Trust
- University of Melbourne
- Peter MacCallum Cancer Centre
- Medical Research Council