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

## TL;DR

This study explores how mutations in the KIF11 gene cause a rare syndrome involving microcephaly, lymphedema, and eye issues, focusing on how these mutations affect the lymphatic system.

## Contribution

The study provides the first evidence linking KIF11 to lymphatic development and dysfunction in MLC syndrome.

## Key findings

- Patients with MLC syndrome have reduced KIF11 mRNA and protein levels due to pathogenic stop-gain variants.
- KIF11 is expressed in lymphatic markers during early human and mouse development.
- Inhibiting EG5 (KIF11) reduces lymphatic cell migration and sprouting, linking KIF11 to lymphangiogenesis.

## 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.

Ogmen et al., studies how pathogenic variants in kinesin KIF11 underlie microcephaly-lymphedema-chorioretinopathy (MLC) syndrome, how KIF11 (encoding EG5) associates with the development of the lymphatic system, and how KIF11 pathogenic variants lead to lymphatic dysfunction and lymphedema.