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

Area of Science:

• Genetics
• Developmental Biology
• Cell Biology

Background:

• Microcephaly-lymphedema-chorioretinopathy (MLC) syndrome is linked to pathogenic variants in the kinesin KIF11.
• KIF11 (EG5) is crucial for cell division, but its role in lymphatic system development and lymphedema pathogenesis is unclear.

Purpose of the Study:

• To investigate the association between KIF11 pathogenic variants and lymphatic dysfunction in MLC syndrome.
• To elucidate the role of KIF11 in lymphangiogenesis and lymphatic endothelial cell function.

Main Methods:

• Analysis of patient-derived lymphoblastoid cells to assess KIF11 mRNA and protein levels.
• Lymphoscintigraphy and imaging to evaluate lymphatic function in patients.
• Expression analysis of KIF11 during human and mouse development and in zebrafish endothelial precursors.
• In vitro studies using human lymphatic endothelial cells (LECs) with KIF11 inhibition or knockdown.

Main Results:

• MLC patients with KIF11 pathogenic variants showed reduced KIF11 expression.
• Patients exhibited impaired lymphatic function, including reduced tracer absorption and intestinal lymphangiectasia.
• KIF11 is expressed in developing lymphatic tissues and endothelial precursors.
• EG5 inhibition or KIF11 knockdown in LECs impaired cell migration, sprouting, and reduced key lymphangiogenic markers (PROX1, VEGFR3).

Conclusions:

• KIF11 haploinsufficiency contributes to lymphatic dysfunction and lymphedema in MLC syndrome.
• KIF11 plays a significant role in lymphangiogenesis and maintaining lymphatic endothelial cell identity.
• This study establishes a novel link between KIF11 and the molecular drivers of lymphatic development.