The Novel KIF1A Missense Variant (R169T) Strongly Reduces Microtubule Stimulated ATPase Activity and Is Associated With NESCAV Syndrome

Abstract

Síndrome de NESCAV; Kinesina; Microtúbul

Síndrome de NESCAV; Kinesina; Microtubulo

NESCAV syndrome; Kinesin; Microtubule

KIF1A is a microtubule-dependent motor protein responsible for fast anterograde transport of synaptic vesicle precursors in neurons. Pathogenic variants in KIF1A have been associated with a wide spectrum of neurological disorders. Here, we report a patient presenting a severe neurodevelopmental disorder carrying a novel de novo missense variant p.Arg169Thr (R169T) in the KIF1A motor domain. The clinical features present in our patient match with those reported for NESCAV syndrome including severe developmental delay, spastic paraparesis, motor sensory neuropathy, bilateral optic nerve atrophy, progressive cerebellar atrophy, epilepsy, ataxia, and hypotonia. Here, we demonstrate that the microtubule-stimulated ATPase activity of the KIF1A is strongly reduced in the motor domain of the R169T variant. Supporting this, in silico structural modeling suggests that this variant impairs the interaction of the KIF1A motor domain with microtubules. The characterization of the molecular effect of the R169T variant on the KIF1A protein together with the presence of the typical clinical features indicates its causal pathogenic effect.

This work was supported by the Instituto de Salud Carlos III (Grant No. PI16/01411 to MG and Grant No. CPII18/00027 to AS), the Asociación Española de Síndrome de Angelman, Institut d’investigació i innovació Parc Taulí I3PT (CIR2018/021), the Ministerio de Educación, Cultura y Deporte (Grant No. FPU16/01099 to MM), the Asociación Española Contra el Cáncer (Grant No. LABAE18009SEGU to MS), and the Centro de Investigación Biomédica en Red Cancer - CIBERONC (Grant No. CB16/12/00363 to SH). Finally, AJ was supported by the Wellcome Trust though a Senior Research Fellowship (202811).