A stuttering-associated Gnptab variant alters fine-motor kinematics

Precise reach-to-grasp movements rely on complex cortico-basal ganglia and cerebellar circuits, and can be affected by cellular pathway defects. We investigated whether mild Gnptab deficiency, affecting mannose-6-phosphate-dependent lysosomal enzyme targeting, impairs fine motor behaviors in mice. Using the staircase test, high-frame-rate video, and markerless tracking, we assessed reaching and grasping in Gnptab-mutant and control littermates. Our data suggest that Gnptab-mutant mice retrieved about 75% fewer pellets than controls and exhibited abnormal grasping, characterized by increased wrist extension and larger digit angles, decreased digital velocity, and shorter reach distances, while elbow angles remained largely unchanged. These findings suggest a specific deficit in grasp shaping and trajectory control, rather than overall limb positioning. Our data establishes a quantitative link between GNPTAB-related lysosomal pathway disruption and fine-motor impairments, providing a valuable model for understanding how cellular dysfunction impacts motor circuit function.