Unraveling the link between KIF13A gene mutation and motor neuron disorder

Brown–Violette–Van-Laere syndrome (BVVLS) is a childhood-onset motor neuron disorder. Autosomal recessive mutations in riboflavin transporter genes can be identified in half of the patients, and the genetic cause is not known for the rest. Recently, we performed whole exome sequencing in a family with five siblings diagnosed with BVVLS and identified an autosomal recessive missense variant in the KIF13A gene that codes for a kinesin motor protein. In this study, we aimed to explore the role of KIF13A in motor neuron degeneration.We first transfected 293T cells with wild-type (WT) and mutant (MT) versions of GFP-tagged KIF13A plasmids to explore the subcellular localization of KIF13A. Then, patient-derived iPSCs were generated and differentiated into MNX1+ human motor neurons (hMNs). Intracellular localization of endogenous KIF13A was examined in iPSCs using immunostaining. Next, neurite growth analysis was conducted.We observed that MT KIF13A tends to be present in aggregates when overexpressed in 293T cells. The staining of KIF13A, alongside B-III tubulin in hMNs and MAP2 in rat cortical neurons, illustrated the distribution of KIF13A along motor neuron axons and dendrites of hMNs and rat cortical neurons respectively.Our preliminary data from neurite growth analysis revealed a reduction in neurite formation in MNs derived from patients when compared to healthy MNs. Mutant and wild-type KIF13A was observed both in the nucleus and cytoplasm but mutant KIF13A mostly resided in the cytoplasm.Our results show that mutations in KIF13A gene may be associated with BVVLS via defects in intracellular transport and neurite formation.