Dominantly acting KIF5B variants with pleiotropic cellular consequences cause variable clinical phenotypes

Area of Science:

• Cell Biology
• Genetics
• Developmental Biology

Background:

• Kinesins are essential motor proteins for intracellular transport, crucial for cellular processes like trafficking and division.
• Mutations in kinesin genes cause diverse human diseases, including neurodevelopmental disorders and ciliopathies.
• KIF5B, an ubiquitous kinesin-1 isoform, plays a vital role in cellular transport, but its pathogenic variants were less understood.

Purpose of the Study:

• To investigate the clinical and molecular consequences of novel dominantly acting KIF5B variants.
• To expand the understanding of the phenotypic spectrum associated with KIF5B dysfunction.
• To elucidate the impact of KIF5B variants on cellular organization and development.

Main Methods:

• Identification and characterization of three novel KIF5B variants (p.Asn255del, p.Leu498Pro, p.Leu537Pro).
• In vitro and in vivo analyses to assess the functional impact of these variants on cellular processes.
• Zebrafish model studies to evaluate developmental effects of KIF5B variants.

Main Results:

• The identified KIF5B variants result in a broad phenotypic spectrum, including dilated cardiomyopathy, ophthalmoplegia, skeletal myopathy, and neurodevelopmental conditions with hypotonia and seizures.
• These variants disrupt the organization of lysosomes, autophagosomes, and mitochondria, and impair cilium biogenesis.
• Zebrafish studies demonstrated that KIF5B variants affect multiple developmental processes, confirming their pathogenic role.

Conclusions:

• Aberrant KIF5B function due to pathogenic variants has pleiotropic consequences on cellular homeostasis and development.
• These findings expand the known phenotypic spectrum of kinesin-mediated disorders.
• KIF5B is a significant contributor to human disease, highlighting the importance of intracellular transport in development and health.