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

Cinthia Aguilera,Anna Santamaria,Anna Ruiz,Stefan Hümmer,Miriam Guitart,Elisabeth Gabau,Marc Masanas,Miguel F Segura,A Arockia Jeyaprakash

doi:10.3389/fnins.2021.618098

Abstract

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.

Highlights

The kinesin superfamily of proteins (KIFs) are microtubule-dependent molecular motors that participate in the transport of membrane vesicles, organelles, protein complexes, and mRNAs along microtubules, playing important roles including mitosis, meiosis, and transport of cellular cargo such as axonal transport (Hirokawa et al, 1989)
KIF1A encodes a neuron-specific motor protein that plays an important role in anterograde axonal transport of synaptic vesicle precursors
Pathogenic variants in the KIF1A gene have been associated with a wide spectrum of neurological phenotypes (Nemani et al, 2020) ranging from recessive hereditary sensory neuropathy-type IIC (HSNIIC) to autosomal recessive or dominant hereditary spastic paraplegia 30 (SPG30) and to the most severe NESCAV syndrome (NESCAVS)

Summary

Introduction

The kinesin superfamily of proteins (KIFs) are microtubule-dependent molecular motors that participate in the transport of membrane vesicles, organelles, protein complexes, and mRNAs along microtubules, playing important roles including mitosis, meiosis, and transport of cellular cargo such as axonal transport (Hirokawa et al, 1989). Novel KIF1A Missense Variant R169T kinesins and is a neuron-specific protein composed of an N-terminal motor domain (MD) (1–361 aa), which contains the ATPase activity and the microtubule-binding domains. These domains are followed by a short-strand “neck linker” (353– 361 aa) and a neck coil region (NC) (365–397 aa) which are key regulatory elements for kinesin-3 motor dimerization and processive motility. KIF1A exists in a dimeric inactive state that is maintained by autoinhibitory mechanisms and are activated upon cargo binding, enabling KIF1A to transport synaptic vesicle precursors along microtubules (Okada et al, 1995; Lee et al, 2003; Hammond et al, 2009)

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