Consequences of KIF13A and SLC49A3 variants in Brown-Vialetto-Van Laere Syndrome using patient-derived iPSCs and motor neurons

Motor neuron diseases (MNDs) constitute a clinically and genetically heterogeneous group of neurodegenerative disorders, characterized by the progressive degeneration of upper and/or lower motor neurons. This degeneration results in muscle weakness, paralysis, and premature death, as exemplified by amyotrophic lateral sclerosis (ALS). Brown–Vialetto–Van Laere (BVVL) syndrome is a rare childhood-onset motor neuron disorder and around half of the cases have been attributed to mutations in the riboflavin transporter genes SLC52A2 and SLC52A3. In the present study, we identified a family with BVVL syndrome negative for mutations in the riboflavin transporters. WES analysis revealed two novel candidate variants: 1) a homozygous single-nucleotide substitution in KIF13A (p. Glu1656Lys) and a heterozygous splice donor mutation in SLC49A3, a solute carrier gene with no prior OMIM association. To investigate their functional consequences, we generated patient-derived motor neurons from induced pluripotent stem cells (iPSCs) and performed molecular, cellular, and transcriptomic analyses. Overexpression assays in HEK293T and SH-SY5Y cells, as well as patient-derived motor neurons, revealed that wild-type KIF13A preferentially localized to dendrites, whereas the mutant variant exhibited reduced dendritic selectivity. Functionally, patient-derived motor neurons displayed significant reductions in neurite outgrowth, axonal elongation, and axonal branching. Transcriptomic profiling further demonstrated upregulation of developmental transcription factors and downregulation of genes involved in axonogenesis, presynaptic differentiation, and axon guidance, consistent with incomplete motor neuron maturation. Together, these results indicate defects in neuronal maturation and axonal elongation in BVVL, providing new mechanistic insights beyond riboflavin transporter deficiency.