Insights intoKIF11pathogenesis in Microcephaly-Lymphedema-Chorioretinopathy syndrome: a lymphatic perspective

Abstract

AbstractPathogenic variants in kinesinKIF11underlie microcephaly-lymphedema-chorioretinopathy (MLC) syndrome. Although well known for regulating spindle dynamics ensuring successful cell division, the association ofKIF11(encoding EG5) with development of the lymphatic system, and howKIF11pathogenic variants lead to lymphatic dysfunction and lymphedema remain unknown.Using patient-derived lymphoblastoid cells, we demonstrate that MLC patients carrying pathogenic stop-gain variants inKIF11have 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 byKIF11haploinsufficiency.We reveal thatKIF11is expressed in early human and mouse development with the lymphatic markers VEGFR3, Podoplanin and PROX1. In zebrafish, scRNA-seq identifiedKIF11specifically expressed in endothelial precursors. In human lymphatic endothelial cells (LECs), EG5 inhibition with Ispinesib, reduces VEGFC-driven AKT phosphorylation, migration and spheroid sprouting.KIF11knockdown reducesPROX1andVEGFR3expression, providing for the first time a link betweenKIF11and drivers of lymphangiogenesis and lymphatic identity.