Pathogenic KIF1A variants differentially disrupt axonal trafficking and impede synaptic development.

In isogenic gene-edited human-induced pluripotent stem cell–derived neurons, pathogenic KIF1A variants differentially disrupt axonal trafficking and synaptic development, with loss-of-function delaying maturation and hyperactivity causing aberrant presynaptic patterning.

• Why it matters: Synapse formation during human neurodevelopment is unclear, and KIF1A-associated neurological disorder (KAND) mutations likely impair the microtubule motor’s trafficking roles in synaptogenesis and maintenance.
• What they did: Isogenic gene-edited neurons were used to test null p.C92* and hypoactive p.P305L versus hyperactive p.R350G, measuring neurite outgrowth, synaptic cargo localization, synapse density, presynaptic patterning, and neuronal activity.
• The result: Null and hypoactive variants delay neurite outgrowth, mislocalize synaptic cargoes, and decrease synapse density, producing delayed synaptic maturation, while hyperactive p.R350G supports outgrowth but causes aberrant motility and precocious activity.

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