Every member of the KIF1A.ORG community should have access to scientific and medical literature about KIF1A and KIF1A Associated Neurological Disorder. Here you can find a current list of all pre-prints and publications related to both the KIF1A gene, and to clinical elements of KIF1A Associated Neurological Disorder. For a comprehensive list of publications that reference KIF1A, please view KIF1A research at PubMed.gov.
A NOTE TO KIF1A FAMILIES
KIF1A.ORG is here to help you access and understand KIF1A research. Here are few resources to help:
- Research Simplified blog posts and videos, where we ask researchers to explain their work and scientific concepts in plain language
- Weekly #ScienceSaturday blog posts where we share exciting scientific developments and educational resources with the KIF1A.ORG community — we also summarize recently published KIF1A literature in plain language
- The KIF1A Glossary helps KIF1A families understand scientific and clinical terms you might encounter in research or other scientific communication
- Do you have questions? Contact us at firstname.lastname@example.org
Identification of an in-frame homozygous KIF1A variant causing a mild SPG30 phenotype in a Korean family (March 30, 2023)
Researchers in South Korea worked with a man who started experiencing gait disturbances at 55 years old, without epilepsy or brain atrophy. The man’s siblings were unaffected, but his father also had gait disturbances that began at 65 years of age, so the researchers performed genetic testing on the family. The genetic testing showed that siblings carrying a single copy of the Glu917del mutation were unaffected, indicating this mutation is recessive.
Long-term Observation of a Japanese Patient with a Multiple-system Neurodegenerative Disorder with a Uniallelic de novo Missense Variant in KIF1A (March 8, 2023)
This case study identifies a 37-year-old patient with an L278P KIF1A mutation who experienced progressive optic nerve atrophy and cerebellar ataxia. The study collects longitudinal data including CT scans and MRI to track the progression of brain atrophy, and also notes less commonly observed symptoms including neurogenic bladder.
Active zone protein SYD-2/Liprin-α acts downstream of LRK-1/LRRK2 to regulate polarized trafficking of synaptic vesicle precursors through clathrin adaptor protein complexes (pre-print February 26, 2023)
The authors mutated several genes involved in the sorting of Synaptic Vesicle Precursors and Lysosomes, observing the impact on KIF1A-mediated transport. They found that LRRK2 and AP-3 were mutated or absent, SVPs and lysosomes weren’t properly separated and were transported as SVP-lysosomes. This caused another protein called liprin-α, which binds to KIF1A and helps its attachment to SVP cargo, to transport to SVP-lysosomes, resulting in cargo mislocalization.
Investigating genotype-phenotype relationship of extreme neuropathic pain disorders in a UK national cohort (February 20, 2023)
Researchers performed whole genome sequencing on patients with neuropathic pain, identifying mutations that may contribute to these symptoms. Mutations in genes encoding both KIF1A and its cargo the TrkA receptor were identified among the patients, highlighting the potential relationship between KIF1A and pain sensation.
A de novo low-frequency mosaic variant of KIF1A causes hereditary spastic paraplegia: A literature review (February 12, 2023)
Researchers in Zhengzhou China identified a family in which three children, their father, and their aunt had hereditary spastic paraplegia and an Arg380Pro mutation in KIF1A. Based on the inherited mutation, the researchers performed genetic sequencing on the children’s grandparents. They found that the grandmother, who did not have obvious symptoms, had a gonadal-somatic KIF1A mutation that was passed on, causing variable HSP symptoms among family members.
High-Resolution structures of microtubule-bound KIF1A and its pathogenic variant P305L (pre-print February 3, 2023)
This study resolves the structure of KIF1A as it walks along the microtubule, providing us with new insights into how exactly KIF1A is able to move as quickly and as far as it does compared to other motor proteins. The authors also resolved the structure of the KIF1A mutant P305L, a prevalent and devastating mutation. They were able to determine that structural changes in a part of KIF1A called the K-loop prevented P305L KIF1A from binding to the microtubule properly. The hope is that this K-loop could be a therapeutic target for structure-based drugs, and that this process can determine the structure of other KAND-associated mutations too.
Insight into the regulation of axonal transport from the study of KIF1A-associated neurological disorder (January 19, 2023)
This review from Shinsuke Niwa’s group synthesizes information from 100 papers to summarize our knowledge – and questions – about important elements of KIF1A Biology, including:
- What interacts with KIF1A?
- What types of cargo does KIF1A carry, and how does this cargo being in the wrong place relate to disease symptoms?
- What proteins activate or deactivate KIF1A cargo transport?
- What types of disorders have been associated with KIF1A mutations?
- What are the differences between loss-of-function and gain-of-function mutations in KAND, and why do both contribute to disease?
KIF1A-Associated Neurological Disorder: An Overview of a Rare Mutational Disease (January 19, 2023)
This review screened 2980 records to find 114 relevant studies and reports relating to KIF1A and KAND. In addition to a brief summary of KIF1A function and structure, this review focuses on diseases associated with KAND spanning a wide variety of symptoms, including Hereditary Spastic Paraplegia, NESCAV Syndrome, PEHO Syndrome, and Autism and Spectrum Disorder.
End Binding Protein 1 promotes specific motor-cargo association in the cell body prior to axonal delivery of Dense Core Vesicles (pre-print January 12, 2023)
Researchers investigated the interactions between End Binding Protein 1 (EBP1), a microtubule-binding protein, and KIF1A. Loss of EBP1 causes Dense Core Vesicles, normally carried by KIF1A, to stall in the cell body instead of being transported along the axon. Deleting specific sections of EBP1 indicated its role in attaching Dense Core Vesicles to KIF1A for subsequent transport.
KIF1A is kinetically tuned to be a super-engaging motor under hindering loads (January 10, 2023)
KIF1A is often called a hyperprocessive motor—that is, KIF1A can move very quickly without cargo. However, kinesin movement may be resisted by cargo or microtubule modifications, raising the question of how KIF1A behaves when it’s resisted. This paper utilizes optical tweezers to demonstrate that KIF1A detaches from the microtubule under resistance, but it reassociates incredibly quickly—often within 2 milliseconds. This high rate of reengaging the microtubule may make KIF1A a more robust transporter when it encounters obstacles, which could play a role in its ability to transfer cargo along very long axons.
Lattice light-sheet microscopy and evaluation of dendritic transport in cultured hippocampal tissue reveal high variability in mobility of the KIF1A motor domain and entry into dendritic spines (January 7, 2023)
In this paper, authors performed an in-depth investigation of KIF1A’s location and movement in and out of the dendrites of CA1 hippocampal neurons in mouse brain slices. This study identified that in these neurons’ dendrites, KIF1A movement is variable: it can engage in long continuous movements in one direction, switch direction rapidly, or stall in place. While all of these states were observed, KIF1A seems to prefer long continuous movement in one direction.
Prenatal isolated clubfoot increases the risk for clinically significant exome sequencing results (November 3, 2022)
Researchers performed genetic sequencing on 38 children who had been diagnosed with prenatal clubfoot and found four cases of genetic mutations, including KIF1A. All four genes are involved in musculoskeletal or neural development and likely to cause or contribute to foot deformities. These symptoms have been observed in other families with KIF1A mutations, both in individual studies and anecdotally, but we don’t know the prevalence in our community.
Genetic and clinical landscape of childhood cerebellar hypoplasia and atrophy (October 28, 2022)
In this study, the authors performed genetic sequencing of children with cerebellar hypoplasia and/or atrophy to look for potential causative mutations for neurodevelopmental or neurodegenerative symptoms. Disease causing variants were identified in 105/188 patients, including 8 patients with KIF1A mutations. Notably, the degree of cerebellar loss was highly variable within the KIF1A group, likely reflecting mutation heterogeneity in our community.
KIF1A novel frameshift variant p.(Ser887Profs*64) exhibits clinical heterogeneity in a Pakistani family with Hereditary Sensory and Autonomic Neuropathy Type IIC (October 25, 2022)
In this study, researchers performed genetic testing on a Pakistani family affected by hyperkeratonic skin disorders, ulcers, and sensory neuropathy, finding a frameshift mutation in KIF1A. The mutation was recessive; while heterozygous patients only had skin dryness, homozygous patients required limb amputations and suffered from sensory loss.
Association of variants in the KIF1A gene with amyotrophic lateral sclerosis (October 26, 2022)
In this study, researchers in China performed genetic analysis of over 8000 patients diagnosed with ALS, and found 45 instances of KIF1A mutations. A subgroup with mutations in KIF1A’s cargo-binding domain had self-reported sensory disturbances, and some of these mutations caused KIF1A to bind too tightly to cargo. This is another example of the heterogeneity of KIF1A mutations, causing different clinical presentations.
Tau Differentially Regulates the Transport of Early Endosomes and Lysosomes (October 20, 2022)
This study investigated the impact of low and high tau concentrations on kinesin-1 and kinesin-3 movement. Both kinesin-1 and KIF1A movement were inhibited by high levels of tau. Notably, phosphomimetic tau eased kinesin-1 movement but further inhibited KIF1A movement. Furthermore, the KIF1A-enriched cell periphery was tau-depleted, indicating potential competition for tubulin between tau and KIF1A.
A Novel de novo KIF1A Mutation in a Patient with Ataxia, Intellectual Disability and Mild Foot Deformity (October 13, 2022)
In this clinical study, researchers performed genetic testing on a patient with ataxia and foot deformities. Alongside a clinical assessment, the authors found that the patient’s ataxia symptoms stabilized after a 4-week ataxia-specific rehabilitation program.
Effect of detachment of motor protein from track on its transport (October 03, 2022)
This paper utilizes existing experimental data of kinesin motors to model the relationship between a motor’s speed and the time it spends attached to the microtubule. This model indicates that faster motors have a higher detachment probability because each motor head must attach and detach for each step.
Kinesin-1, -2 and -3 motors use family-specific mechanochemical strategies to effectively compete with dynein during bidirectional transport (September 20, 2022)
In this study, single kinesin and dynein complexes were tethered to investigate bidirectional competition. There were three patterns of movement for kinesin-dynein pairs. During paused periods, the dynein anchored itself in an inactive state and couldn’t be moved by the kinesins. During fast periods, dynein-tethered kinesins moved toward the plus end almost as fast as untethered kinesin, possibly because dynein was only loosely attached to the microtubule. During slow periods, the dynein and kinesin engaged in a tug-of-war that resulted in very slow movement. This supports that rather than constantly engaging in tug-of-war, motor proteins are likely differentially activated by adaptor proteins to determine protein transport.
Investigating KIF1A mutations in a Taiwanese cohort with hereditary spastic paraplegia (September 16, 2022)
KAND is a genetic disorder that is associated with symptom-defined diseases like hereditary spastic paraplegia (HSP). Researchers from Taiwan tested for KIF1A mutations among HSP patients. Out of 242 patients tested, 3 were found to have KIF1A mutations: Two of these mutations (R316Q and G321D) are already associated with KAND, while the third (E19K) is a novel mutation in the motor domain that hasn’t been characterized as KAND-causing. By investigating symptoms in these people and their family members, the authors were able to find that disease progression can vary between parents and children carrying the same mutations.
Single-Molecule Studies on the Motion and Force Generation of the Kinesin-3 Motor KIF1A (September 6, 2022)
This is a set of standardized protocols to study molecular traits of KIF1A. The assays include generating active dimerized KIF1A, KIF1A mutagenesis, MT-binding and -release assay, TIRF microscopy, and optical tweezers.
Huntingtin-KIF1A-mediated axonal transport of synaptic vesicle precursors influences synaptic transmission and motor skill learning in mice (pre-print August 15, 2022)
Constitutively active huntingtin associates with KIF1A and increased its movement of synaptic cargo to the ends of neuronal axons. As a result, neurons with overactive HTT transport were also more electrically active and less likely to strengthen connections than neurons with normal HTT. Mice carrying this mutation weren’t able to learn or perform new motor skills as well as healthy mice. Because permanently phosphorylated HTT seemed to be transported by KIF1A, the authors then knocked down KIF1A protein by 83% in mice with mutant HTT. They found that this decreased the amount of synaptic vesicle transport, and restored some of the motor learning deficits in mice. Notably, knocking down KIF1A in mice with normal HTT caused many synaptic vesicles to move in reverse, which may cause other types of neuronal dysfunction.
Force generation of KIF1C is impaired by pathogenic mutations (August 11, 2022)
Mutations in KIF1C can cause hereditary spastic paraplegia, tremors, and cerebellar movement disorders. In this study, researchers used optical tweezers to study motor properties of healthy KIF1C, and KIF1C carrying disease-relevant mutations. Unburdened KIF1C motors were allowed to run without any cargo, they were quicker than healthy KIF1C, but less likely to make it to their destination — they lacked traction and had a higher rate of falling off of the microtubule early. When these mutants were attached to cargo, including microbeads and large cell structures called mitochondria, they generated less force than their healthy counterparts.
Kinesin-3 motors are fine-tuned at the molecular level to endow distinct mechanical outputs (August 10, 2022)
This study investigated four members of the kinesin-3 family: KIF1A, KIF13A, KIF13B, and KIF16B, and found that their fast-stepping pace closely matches the rate at which they turn over ATP. This high ATP turnover only occurred when the kinesin-3 motors were in their active state. KIF1A was the fastest motor in the kinesin-3 family and had the lowest affinity for microtubules, meaning it stuck to the microtubule less than other motors. This trait was mediated by a motor domain called loop8: Mutating positively charged sections of loop8 in KIF1A changed KIF1A’s microtubule affinity and ability to transport cargo to cell processes.
De novo mutations in KIF1A-associated neuronal disorder (KAND) dominant-negatively inhibit motor activity and axonal transport of synaptic vesicle precursors (August 9, 2022)
This study introduced heterozygous mutations to C. elegans that match the KAND mutations R11Q, R254Q, and P305L. These worms had reduced movement, and KIF1A cargo ended up in the wrong places within neurons. The findings suggest that when mutant KIF1A and healthy KIF1A cooperate to carry a cargo, the mutant KIF1A holds healthy KIF1A back. Suppressor screens identified a mutation that restored KIF1A movement by changing the protein’s charge and increasing its ability to bind to the microtubule.
The architecture of kinesin-3 KLP-6 reveals a multilevel-lockdown mechanism for autoinhibition (July 25, 2022)
This paper characterizes the structure of KLP-6, a kinesin-3 family member expressed in C. elegans. The authors were interested in understanding the neck region of KLP-6 – in most kinesins the neck is thought to participate in autoinhibition, the process of shutting down motor movement until an appropriate cargo has been bound. The authors found that several domains in the neck cooperate to successively shut down dimer formation, motor activity, and microtubule binding. Disrupting the structure of these inhibitory domains increased KLP-6 movement. The researchers compared KLP-6 and KIF1A structure and hypothesized that mutations in these inhibitory domains could contribute to hyperactive KIF1A, which could have implications for the way KAND manifests in these patients.
Functional Investigation of TUBB4A Variants Associated with Different Clinical Phenotypes (June 6, 2022)
In this paper, researchers investigated distinct and common features of patients with a mutation in TUBB4A, a type of tubulin enriched in the central nervous system. These mutations are associated with epilepsy, spasticity, and a hypomyelination. Most mutations caused changes in microtubule formation and decreases in axon growth, but this was not observed in the mutation causing the mildest symptoms. The authors also found that two of these mutations impaired microtubule’s ability to bind KIF1A, which could contribute to symptoms similar to KAND.
A kinesin-1 variant reveals motor-induced microtubule damage in cells (May 2, 2022)
This paper investigates a mutation in KIF5C, a kinesin-1 family member. This mutation resulted in KIF5C moving faster than normal while generating less force with each step. The authors found that this form of KIF5C caused microtubules to bend, knot, and eventually break. While microtubules break and repair themselves under normal conditions, mutant KIF5C caused damage too drastic for repair processes to overcome. They directly compared this to a constitutively active KIF1A protein, which they found did not cause the same level of microtubule breakage.
Selective axonal transport through branch junctions is directed by growth cone signaling and mediated by KIF1/kinesin-3 motors (April 26, 2022)
This study investigates what factors bias kinesins to carry cargo to one axon terminal or the other. Neuronal axons often have multiple branches. By watching cargo “choose” where to go at the point where branches break off from the main axon, researchers learned more about what impacted this choice. They found that the kinesin-bound cargo synaptophysin, which regulates synaptic growth, was more likely to travel along the main axon, especially when the branches were shorter. However, whether an axon was growing had a much bigger impact on the cargo’s direction than axon length. Kinesin-3 family proteins (of which KIF1A is a member) were more responsive to these factors than other kinesins.
Intragenic suppressors of unc-104 [KIF1A] (e1265) identify potential roles of the conserved stalk region (April 6, 2022)
This micro-paper investigates the stalk domain of KIF1A (called unc-104 in the C. elegans worm model). Researchers were studying a KIF1A mutation in the cargo-binding domain (e1265) that impairs worm movement. They then utilized a suppressor screen — worms were subjected to random secondary mutations until their movement recovered, and these random mutations were identified. The initial cargo-binding mutation was suppressed by three secondary mutations. The authors hypothesize that secondary mutations in the stalk region may prevent KIF1A from folding up so that it can continue moving with whatever cargo it is able to bind.
ALS-associated KIF5A mutations abolish autoinhibition resulting in a toxic gain of function (April 5, 2022)
KIF5A proteins usually stay dormant until binding to another KIF5A as well as a cargo, a process called autoinhibition. Mutations can alter the part of KIF5A responsible for this autoinhibition, making the protein active at all times, which can cause KIF5A to accumulate away from the cell body. This article assesses KIF5A gain-of-function mutations using a variety of cell lines, including patient-derived neuronal cultures. The study found that mitochondria, which provide energy for cellular processes, move faster along axons when carried by mutant KIF5A, which could underlie energetic failure and neurodegeneration seen in ALS.
Kif15 Is Required in the Development of Auditory System Using Zebrafish as a Model (March 18, 2022)
In mammals, the auditory system works through our cochlea, and the vestibular systems works through our inner ear organs. Both rely on sensory cells called “hair cells”, which activate when pressure pushes them in one direction. In zebrafish, the auditory and vestibular systems both exist in the inner ear organs. Researchers reduced expression of KIF15 in zebrafish and found that inner ear development was disrupted, including a loss of hair cells. Because hearing and balance are both crucial for proper movement in zebrafish, their locomotion was severely reduced as well. These functions were rescued when KIF15 knockdown was co-injected with KIF15 mRNA to restore protein levels to normal.
A neuropathy-associated kinesin KIF1A mutation hyper-stabilizes the motor-neck interaction during the ATPase cycle (February 8, 2022)
This paper characterizes an E239K KIF1A variant that has recently been identified in a family with axonal-type Charcot-Marie-Tooth disease as well as in 24 cases of human neuropathies. On a clinical level, we learn of two brothers between 60 and 70 years of age who have both experienced late onset, yet progressive, neurological symptoms such as muscle atrophy, weakness and balance difficulties. Mechanistically, it is revealed that the E239K mutation significantly impairs the transport velocity of common KIF1A cargos in axons caused by ATP hydrolysis impairment. Additionally, this paper uncovered a structural interaction between the KIF1A neck linker and E239 in the beta-7 strand of the KIF1A motor domain.
Finding a cure for the rare but severe KIF1A Associated Neurological Disorder, what we (need to) know (February 6, 2022)
Looking for a great summary discussing KIF1A biology, KAND basics, as well as potential KAND treatments and cures? This review-style paper covers all the above topics and more. We think this is a great resource to help us understand the big picture history of our KIF1A understanding and how the discovery of KIF1A mutations have shaped and influenced the field of KIF1A research over time. Additionally, this paper breaks down what we know about a select handful of mutations—from how these mutations impact KIF1A function on a molecular level to how they may present on a clinical level—and how this information can inform us about potential treatments for KAND.
Illustration of a rare case of hereditary spastic paraplegia type 30 associated with a missense variant in the non-motor domain of KIF1A (January 9, 2022)
This Letter to the Editor style paper tells the story of a 40-year-old patient diagnosed with a rare case of hereditary spastic paraplegia type 30 thought to be caused by a mutation in the KIF1A gene. While not initially diagnosed with KAND, this patient presented with many KAND symptoms starting as early as age 10, including irregular gait patterns, cognitive impairment, cerebellar atrophy and neuropathy. When whole-exome sequencing was performed on this patient, the results revealed a heterozygous KIF1A R1296H mutation. Importantly, the mutation highlighted in this paper is located outside of the motor domain.
Neurogenetic disorders across the lifespan: from aberrant development to degeneration (January 5, 2022)
The perspectives-style paper, co-authored by KIF1A Research Network member and KAND clinical champion Dr. Wendy Chung, highlights several neurogenetic disorders that have developmental and degenerative overlap in the context of intellectual disability and autism spectrum disorder, including KIF1A Associated Neurological Disorder. This paper goes on to discuss many considerations around this topic such as shared mechanisms of disease, the need to study neurogenetic disorders across a patient’s full lifespan, the importance of a natural history study, and the relevance of familial genetic testing.
Clinical and genetic spectra of 1550 index patients with hereditary spastic paraplegia (January 4, 2022)
In this paper, researchers investigated the genetic causes of 1550 patients who have been clinically diagnosed with hereditary spastic paraplegia (HSP). Like we commonly see when genetic screens are performed on large clinical cohorts with neurodevelopmental or neurodegenerative symptoms, the KIF1A gene was one of the genes identified in this cohort of 1550 HSP patients, albeit one of the rarest genes identified, representing about 1% of patients sampled. From this study we get further confirmation of the significant role that the KIF1A gene plays in a broad range of neurodegenerative and/or neurodevelopmental disorders.
Hemorrhagic shock and encephalopathy syndrome in a patient with a de novo heterozygous variant in KIF1A (December 13, 2021)
***As a disclaimer, the summary below and full paper describes a severe clinical example of KAND manifestation, which can be distressing to read***
This report reviews the case of a 3-year-old girl with a E253K variant in the KIF1A gene. Symptoms were captured and assessed as early as five months old presenting as developmental delay, epileptic discharge and severe axonopathy of both motor and sensory nerves. At six months, the patient required intensive care for a variety of symptoms such as acute encephalopathy, multiple organ failure and disseminated intravascular coagulation. This led to the additional diagnosis of hemorrhagic shock and encephalopathy syndrome. This is case report confirms that E253K can be a KIF1A variant with severe neurological features and systemic implications.
Initiation of ensemble kinesin-3 motility is regulated by the rigidity of cargo-motor attachment (December 2, 2021)
This preprint article helps uncover the role of KIF1A in molecular motor ensemble cargo transport by investigating the behavior of artificially engineered KIF1A motor teams. Specifically, this study focuses on how KIF1A motors are linked or attached to cargo and how this linkage may impact KIF1A team cargo transport. From this study, authors find that there are differences in cargo transport between KIF1A motors that are loosely linked to cargo (more flexible) vs. KIF1A motors that are tightly linked to cargo (more rigid).
Motor domain-mediated autoinhibition dictates axonal transport by the kinesin UNC-104/KIF1A (November 29, 2021)
In this paper, researchers described a new form of KIF1A autoinhibition. Although KIF1A autoinhibition has been reported in the past, the study details a new form of autoinhibition that is mediated between two regions of the KIF1A protein, the motor domain and the CC1 domain. Furthermore, the authors identified KIF1A variants within these regions that impact KIF1A autoinhibition and shift the KIF1A motor into a hyperactive state.
Specific KIF1A-adaptor interactions control selective cargo recognition (October 4, 2021)
In this study, researchers engineered motors and cargo adaptors to investigate the selectivity and regulation of KIF1A-driven transport of key KIF1A cargos. Specifically, this study sheds new light on the role of key KIF1A protein domains, showing that the CC1 domain regulates autoinhibition, CC2 regulates motor dimerization, and CC3 and PH mediate cargo binding. Additionally, the role of post-translational modifications like phosphorylation was investigated in relation to KIF1A cargo binding. In summary, this work “proposes a model where motor dimerization, posttranslational modifications, and specific adaptors regulate selective KIF1A cargo trafficking”.
Intracellular force comparison of pathogenic KIF1A, KIF5, and dynein by fluctuation analysis (September 15, 2021)
In this pre-print article, this research team investigated how three KAND variants (V8M, A255V, and R350G) may impact the force and velocity of the KIF1A motor while transporting a KIF1A-relevant cargo using non-invasive force measurement in mammalian neuronal cultures. They observed that the V8M and A255V variants resulted in impaired force and velocity measurements meaning that the introduction of these variants makes the KIF1A motor slower and not as strong. However, the R350G variant showed little change and had similar properties to the wild-type (non-mutated) KIF1A motor.
Monoallelic KIF1A‑related disorders: a multicenter cross sectional study and systematic literature review (September 6, 2021)
In this paper, a group of researchers review their findings from a multicenter study conducted in patients with heterozygous KIF1A mutations and presenting with spastic gait or complex neurodevelopmental disorders. Additionally, this group conducted a comprehensive literature review to compare their findings with previously-reported KIF1A-related phenotypes. Of the 28 patients observed, 17 mutations occurred within the motor domain of KIF1A with no correlation found between disease severity and mutation location. Additionally, this study performed muscle biopsies, showing that 40% of patients had oxidative damage and impaired lipid metabolism in skeletal muscle.
Evaluation of candidate genes in a Chinese cohort of atypical Rolandic epilepsy (August 1, 2021)
In this study, researchers explore and verify candidate genes, one of which is KIF1A, that are linked to atypical Rolandic epilepsy by using whole-exome sequencing (WES) analysis in a cohort of twenty-four patients. Specifically, two atypical Rolandic epilepsy patients were identified to have KIF1A mutations, making up over 8% of the study’s cohort. This study provides an important genetic link between certain KIF1A mutations and atypical Rolandic epilepsy.
De novo disease-associated mutations in KIF1A dominant negatively inhibit axonal transport of synaptic vesicle precursors (Jul 23, 2021)
In this manuscript, Dr. Niwa and his team in Japan focused heavily on establishing a KAND model in C. elegans via the CRISPR/Cas9 system that will be useful in analyzing the molecular biology of the disease in vivo. Additionally, their work showed evidence that KIF1A disease mutants significantly impair the motility of wild-type KIF1A when KIF1A heterodimers are formed, which then inhibits axonal transport as a whole. Through this research, they hope to provide more insight on the effects of mutant KIF1A and contribute a foundational worm model that can be used for drug screenings to find future KAND therapies.
Specific KIF1A–adaptor interactions control selective cargo recognition (Jul 21, 2021)
In this paper, scientists identify the KIF1A domains that contribute to the function of KIF1A motor activity and show that CC1 regulates autoinhibition, CC2 regulates motor dimerization, and CC3 is involved in cargo interaction. Their investigations led them to conclude that specific KIF1A adaptors, such as Arl8A and MADD, are responsible for directing cargo to their specific locations within cells. Overall, their research focuses on uncovering the different forms of regulation that contribute to the selective KIF1A cargo trafficking that is so essential to proper brain function and development.
Bioinformatics Analysis of KIF1A Expression and Gene Regulation Network in Ovarian Carcinoma (Jun 6, 2021)
To determine if there is any clinical significance of KIF1A expression levels in ovarian cancer (OC), especially in the development of the disease, researchers compared expression levels of KIF1A in OC tissue with that in normal tissue. Seeing that KIF1A was highly elevated in OC tissues, they proposed that KIF1A can be a promising biomarker for OC that can significantly help patients with the prognosis of this disease.
The Novel KIF1A Missense Variant (R169T) Strongly Reduces Microtubule Stimulated ATPase Activity and Is Associated With NESCAV Syndrome (May 26, 2021)
From data collected from whole exome sequencing, these researchers identified a novel KIF1A variant that has been identified with clinical features that match those of NESCAV Syndrome. Additionally, they determined that this KIF1A variant (R169T) impairs KIF1A’s ATPase activity by disrupting the motor’s ability to bind to microtubules via the motor domain, giving more insight into the causes of neurodevelopmental disorders.
Kinesin-3 mediated delivery of presynaptic neurexin stabilizes growing dendritic spines and postsynaptic components in vivo (May 11, 2021)
In this article, researchers highlight NRX-1’s role in synapse development and function by showing how the deletion of NRX-1 disrupted the normal growth of neurons and led to the improper localization of key components in synapses. They also demonstrate that kinesin-3/UNC-104 mediates the delivery of the NRX-1 protein necessary for synapse stabilization and maturation, all of which is essential for the developmental progression of mature neurons, synapses, and connections.
A highly conserved 310 helix within the kinesin motor domain is critical for kinesin function and human health (April 30, 2021)
To gain a better understanding of the missense mutation, P305L, that causes KIF1A-Associated Neurological Disorder (KAND), researchers used biochemical and single-molecule approaches to elucidate the molecular basis of this disease. As the mutant most significantly affects KIF1A’s microtubule-association rate, it is proposed that the P305 residue, located in the 310 helix adjacent to the K-loop, plays an important role in facilitating the K-loop confirmation that is critical for motor function.
Genotype and defects in microtubule-based motility correlate with clinical severity in KIF1A Associated Neurological Disorder (April 8, 2021)
In this study, researchers coin a new way to describe KAND subtypes and depict the spectrum of disease severity by characterizing a natural history of KAND in 117 individuals to develop a heuristic severity score. Their findings showed that increased severity was associated with certain regions in KIF1A and that all patient variants led to defects in transport, such as reduced microtubule binding, reduced velocity and processivity, and increased non-motile rigor microtubule binding.
A Novel Synergistic Association of Variants in PTRH2 and KIF1A Relates to a Syndrome of Hereditary Axonopathy, Outer Hair Cell Dysfunction, Intellectual Disability, Pancreatic Lipomatosis, Diabetes, Cerebellar Atrophy, and Vertebral Artery Hypoplasia (February 6, 2021)
Scientists in India conducted a case study on a 19-year old girl who seems to be the first patient to have a neuro-pancreatic syndrome (NPS) that resulted from concurrent mutations in both the PTRH2 and KIF1A genes. This paper discusses the patient’s symptoms in detail to characterize this unique disease presentation in order to provide novel insight and raise awareness for rare disorders that fall in the wide spectrum of NPS.
Molecular Diagnostic Yield of Exome Sequencing in Patients With Cerebral Palsy (February 2, 2021)
With cerebral palsy (CP) being a common neurodevelopmental disorder, researchers set out to determine the molecular diagnostic yield of exome sequencing (ES), or the prevalence of pathogenic and likely pathogenic variants, in patients with CP. In the two cohorts of CP patients that underwent ES, the molecular diagnostic was determined to be 32.7% among a predominantly pediatric group, thus showing the value and benefits of ES for accurate diagnoses.
Pathogenic mutations in the kinesin-3 motor KIF1A diminish force generation and movement through allosteric mechanisms (January 26, 2021)
To gain a deeper understanding of the force-generating properties of KIF1A, scientists collaborated to uncover KIF1A’s weak force generation and rapid reattachment ability to microtubules to resume motility. By introducing disease-relevant mutations that impair neck linker docking, they demonstrated that mutations in KIF1A dramatically reduced force generation, but not the motor’s reattachment ability, advancing insights regarding KIF1A mutations in human disease.
Insights From Genetic Studies of Cerebral Palsy (January 21, 2021)
In this paper, researchers comprehensively evaluate key findings in cerebral palsy (CP) genomics and propose a diagnostic criteria for CP-associated genes. The review also discusses the overlap of CP-associated genes in other neurodevelopmental and movement disorders to further highlight the value and accuracy that genetic testing provides. Overall, these researchers emphasize the importance of identifying the genetic etiologies of CP, as it gives more insight on CP pathogenesis and the future developments of CP therapeutics.
PTP-3 phosphatase promotes intramolecular folding of SYD-2 to inactivate kinesin-3 UNC-104 in neurons (November 4, 2020)
Previous studies have shown that SYD-2, a homolog for liprin-α in Caenorhabditis elegans, activates UNC-104, a C. elegans homolog of KIF1A, and is a substrate of PTP-3/LAR PTPPR, a phosphatase. This article discusses the important role PTP-3 phosphatases play in increasing the presence of SYD-2 in folded conformations, which then leads to the inactivation of UNC-104 and its cargo transport.
A kinetic dissection of the fast and superprocessive kinesin-3 KIF1A reveals a predominate one-head-bound state during its chemomechanical cycle (October 20, 2020)
To achieve a better understanding of KIF1A’s chemomechanical cycle and properties, this study used stopped-flow fluorescence spectroscopy and single-molecule motility assay to uncover that the KIF1A forward step triggered by ATP hydrolysis is similar to that found in kinesin-1 and -2. Additionally, scientists found that KIF1A exists in a one-head-bound state for the majority of its hydrolysis cycle and that the rate limiting transition is the attachment of the tethered head. By defining the order of states that make up KIF1A’s chemomechanical cycle and quantifying the transition rates between the states, researchers propose a mechanistic explanation for KIF1A’s superprocessivity, high velocity, and load sensitivity, giving more insight on KIF1A’s evolved and diverse mechanochemistry.
GSK3β Impairs KIF1A Transport in a Cellular Model of Alzheimer’s Disease but Does Not Regulate Motor Motility at S402 (October 16, 2020)
With impaired axonal transport being an early sign of Alzheimer’s disease (AD), researchers were eager to investigate how amyloid-β oligomers (AβOs) associated with AD impair KIF1A function as well as delineate the effects of glycogen synthase kinase 3β (GSK3β) on KIF1A transport. From mass spectrometry on KIF1A, they found that GSK3β was a phosphopeptide targeted by kinases attributed to AD and that phosphorylation at S402 of GSK3β could regulate KIF1A mobility. From their collected data, they concluded that AβOs inhibit KIF1A transport and that GSK3β impairs KIF1A movement, but does not modulate motor motility at S402.
Phenotypic expansion in KIF1A-related dominant disorders: A description of novel variants and review of published cases (September 15, 2020)
In this article, researchers present a novel pathogenic in-frame deletion in KIF1A’s motor domain that was inherited by two siblings with an unaffected mother and identify eight additional cases with pathogenic heterozygous KIF1A variants. Their data demonstrated that KIF1A-associated phenotypes also encompass other clinical features not previously noted, such as hip subluxation and dystonia. They suggest that KIF1A dysfunction is better viewed as a single neuromuscular disorder with variable involvement with other organ systems than as a set of discrete disorders converging at a single locus.
KIF1A-related autosomal dominant spastic paraplegias (SPG30) in Russian families (August 3, 2020)
Aimed to detect the occurrences of autosomal dominant (AD) SPG30 in the Russian population, scientists identified SPG30 in ten unrelated families where all the mutations were located in KIF1A’s motor domain through massive parallel sequencing and whole-exome sequencing. These observations led researchers to believe that AD SPG30 is one of the most common forms of SPG in Russia and is shown to have much clinical variability.
Heterozygous KIF1A variants underlie a wide spectrum of neurodevelopmental and neurodegenerative disorders (July 31, 2020)
By describing the clinical and genetic features seen in 19 Caucasian patients with heterozygous KIF1A variants, this study detected 14 different heterozygous missense variants using next-generation sequencing screening, which included three novel variants. These observations expand the current classification of KIF1A-related disorders and its clinical spectrum, encouraging a KIF1A screening to be conducted for patients diagnosed with HSP or HSP-related disorders.
Expansion of the phenotypic spectrum of de novo missense variants in kinesin family member 1A (KIF1A) (July 11, 2020)
In efforts to expand the understanding of the phenotypic spectrum of de novo missense variants in KIF1A, researchers report on novel de novo KIF1A variants found in patients with Rett syndrome (RTT) [p.(Asp248Glu)] and severe neurodevelopmental disorder with clinical features that overlap with KAND [p.(Cys92Arg) and p.(Pro305Leu)]. Using neurite tip accumulation assays and microtubule gliding assays, they showed that these novel KIF1A variants lessened the ability of KIF1A’s motor domain to accumulate along neurites, as well as reduced KIF1A velocity and microtubule binding. Overall, the results from this study provide more information on the phenotypic characteristics seen in KAND individuals with KIF1A variants in the motor domain, which include common features that are also observed in RTT individuals.
Deletion of the Pseudorabies Virus gE/gI-US9p complex disrupts kinesin KIF1A and KIF5C recruitment during egress, and alters the properties of microtubule-dependent transport in vitro (June 8, 2020)
To further investigate how the pseudorabies virus (PRV) gE/gI-US9p complex affects KIF1A and KIF5C function, researchers at the Albert Einstein College of Medicine prepared Δ(gE/gI-US9p) mutants to study its effects. They found that the loss of the complex had no effect on PRV assembly, but did greatly diminish plus end-directed traffic and enhanced minus end-directed and bidirectional transport on microtubules. Additionally, loss of gE/gI-US9p led to failure in KIF1A and KIF5C recruitment, suggesting a model that shows how the complex binds KIF1A to ensure plus end-directed movement and delivers PRV particles to locations where KIF5C is recruited.
Pseudorabies Virus Infection Accelerates Degradation of the Kinesin-3 Motor KIF1A (April 16, 2020)
With previous studies showing that KIF1A regulates axonal sorting and transport of pseudorabies viruses (PRV), scientists at Princeton University set out to delineate how PRV infection affects KIF1A function. Their studies uncover that PRV infection causes the depletion of KIF1A mRNA and accelerates proteasomal degradation of KIF1A proteins. They identified that the PRV US9/gE/gI protein complex is a viral factor that facilitates the KIF1A degradation in axons during infection by recruiting KIF1A to viral transport vesicles that in turn accelerate deterioration.
A Rare KIF1A Missense Mutation Enhances Synaptic Function and Increases Seizure Activity (February 27, 2020)
At the time with no reports of KIF1A mutations seen in patients with epilepsy, this research team conducted a customized sequencing of epilepsy-related genes in six patients with generalized epilepsy to identify a rare KIF1A mutation (c.1190C > A, p. Ala397Asp) in KIF1A’s neck linker associated with epileptogenesis. In their studies, they also found that the mutant KIF1A increased excitatory synaptic transmission and epileptic seizure-like behavior in their zebrafish model. These results could provide more insight on the clinical spectrum of epileptogenesis, as the mutation that results in increased dendritic spines suggests a possible cause for abnormal neuronal circuits.
KIF1A‐related disorders in children: A wide spectrum of central and peripheral nervous system involvement (February 24, 2020)
To further understand the spectrum of features displayed in KIF1A-related disorders (KRD) aka KIF1A Associated Neurological Disorder (KAND), this study collected data from twelve individuals, where eight different mutations were present collectively with four of them being novel. The observations noted in this case series shows that KAND constitutes a range of neurological disorders on a severity spectrum that shares some common features and combines deficits seen in the central and peripheral (including autonomic) nervous systems.
Generation of a human induced pluripotent stem cell line (SDUBMSi001-A) from a hereditary spastic paraplegia patient carrying kif1a c.773C>T missense mutation (February 4, 2020)
Researchers in China developed induced pluripotent stem cells (iPSCs) by reprogramming peripheral blood cells with non-integrative vectors from a Chinese patient with HSP carrying a c.773C>T(p.T258M) mutation in KIF1A. Data from this iPSC line shows that it had a normal karyotype, expressed pluripotency markers, and could differentiate into three germ layers in vitro. Generating a iPSC line helps provide a cellular model that can be used to investigate the HSP pathogenic mechanism that is related to KIF1A mutations.
A kinesin-3 recruitment complex facilitates axonal sorting of enveloped alpha herpesvirus capsids (January 29, 2020)
As a means to elucidate axonal sorting events, researchers investigate how human herpes simplex virus (HSV-1) and pseudorabies virus of swine (PRV) act as cargo and regulate transport mechanisms. They found that three viral membrane proteins (Us7, Us8, and Us9) form a complex to recruit KIF1A at the trans-Golgi network and that Us9 can increase KIF1A velocity. With evidence that the complex formation helps to mediate efficiency of axonal sorting and motility of capsids, this study provides further insight into the understanding of alpha herpesvirus transport and kinesin-regulated sorting of axonal cargoes.
A Novel de novo KIF1A Mutation in a Patient with Autism, Hyperactivity, Epilepsy, Sensory Disturbance, and Spastic Paraplegia (December 6, 2019)
Another case study details a patient with a novel de novo mutation in the motor domain of KIF1A [c.37C>T (p.R13C)] that is reported to have autism and hyperactivity; however, these symptoms were only seen in patients with a c.38 G>A (R13H) mutation. This observation suggests that alterations in this specific arginine at codon 13 may lead to common clinical signs, which further expands the genotypic and phenotypic spectra associated with KIF1A variants.
Long-term follow-up until early adulthood in autosomal dominant, complex SPG30 with a novel KIF1A variant: a case report (December 3, 2019)
By following a patient case of hereditary spastic paraplegia (HSP) type 30 (SPG30) from infancy to adulthood, this article reports on a de novo heterozygous KIF1A variant (c.914C > T missense) derived from targeted NGS sequencing. This follow-up can be beneficial in bringing more insight regarding the natural history of the disease and its characterization concerning the phenotypic and genotypic variability of SPG30.
Mobility Characteristics of Children with Spastic Paraplegia Due to a Mutation in the KIF1A Gene (December 5, 2019)
In this study, researchers describe the different phenotypes of spastic parapeligia due to KIF1A mutations that are observed in four young patients in the Netherlands. They concluded that de novo KIF1A mutations that lead to spastic parapeligia severely affected children’s mobility and cognition.
Targeted resequencing identifies genes with recurrent variation in cerebral palsy (November 4, 2019)
In order to gain more insight on the genetic aetiology of cerebral palsy (CP), researchers tested 366 cases of CP on a custom gene panel of 112 candidate genes. The data showed evidence of six recurrently hit genes, which contributed to at least 4% of the CP cases (COL4A1, TUBA1A, AGAP1, L1CAM, MAOB and KIF1A). Overall, this study demonstrates the value and clinical utility of genetic testing.
A novel strategy to visualize vesicle-bound kinesins reveals the diversity of kinesin-mediated transport (October 2, 2019)
To uncover how transport is mediated by different kinesins, a novel strategy was developed to visualize kinesins in living cells to determine the localization and transport parameters of vesicles by Kinesin-1, -2, and -3 family proteins that can be used to investigate kinesin function in many cell types. Overall, the study suggests that the vesicle’s identity influences the kinesin’s transport parameter, a term they call “on-vesicle regulation.” More specifically, it was found that Kinesin-3 members partake in a diverse range of localization and transport parameters with the motor binding to at least two distinct vesicle populations.
Going Too Far Is the Same as Falling Short: Kinesin-3 Family Members in Hereditary Spastic Paraplegia (September 26, 2019)
Scientists from Canada and Japan wrote this review on the characteristics of Kinesin-3 family proteins, KIF1A and KIF1C, and their HSP-related mutants, in hopes of encouraging future efforts to concentrate on “transportopathies” that focus on the link between Kinesin-3 cargos and HSP. With the collaborative efforts of many researchers to collect comprehensive data, this article brings a wealth of knowledge regarding our current understanding of kinesin-3, particularly KIF1A, and how these motors behave in disease.
Rett and Rett-like syndrome: Expanding the genetic spectrum to KIF1A and GRIN1 gene (September 11, 2019)
In order to further investigate the causes of Rett syndrome (RTT) or Rett-like phenotypes, researchers in China used targeted next-generation sequencing to find pathogenic variants of KIF1A and GRIN1 that were linked to RTT and Rett-like profiles, expanding the heterogeneity of Chinese RTT or Rett-like patients.
KIF1A variants are a frequent cause of autosomal dominant hereditary spastic paraplegia (September 5, 2019)
Previous studies have shown that KIF1A variants can cause autosomal recessive spastic paraplegia 30, autosomal recessive hereditary sensory neuropathy, or autosomal dominant mental retardation type 9. Recently, using exome sequencing researchers in the Netherlands have identified KIF1A variants can also lead to autosomal dominant spastic paraplegia with the KIF1A motor domain being a hotspot for the observed type of inheritance pattern. They also found that some dominant spastic paraplegia cases were caused by loss-of-function variants outside the motor domain, suggesting haploinsufficiency as a possible mechanism.
Genetic heterogeneity in infantile spasms (July 29, 2019)
A study conducted at the University of Washington sought to better understand the genetic landscape of infantile spasms (IS) by using targeted sequencing to screen candidate IS genes. They found pathogenic variants in KIF1A and a number of other genes, highlighting the genetic heterogeneity of IS.
Genetic testing of >1300 patients with cerebral palsy reveals an etiology in one-third of cases, underscoring the need for broad genetic testing and a significant recurrence risk for families. (P4.6-028) (May 8, 2019)
By studying a cohort of 1346 cerebral palsy (CP) patients that underwent exome sequencing (ES), these researchers found that ES yielded a positive result in 32.7% of the cases. Furthermore, ES revealed that there was a high de novo rate in these cases and that KIF1A and CTNNB1 were the most common positive genes in this group. Overall, the data from this study push for the continued and increased usage of ES to help identify prognosis, therapies, and management options for CP and similar diseases.
Usefulness of exome sequencing in the study of spastic paraparesis and cerebellar atrophy: De novo mutation of the KIF1A gene, a new hope in prognosis (March 10, 2019)
Researchers in Spain conducted a case study on a 7 year-old boy with intellectual disability that underwent multiple tests to determine a diagnosis. Using exome sequencing, researchers found that this technique was more efficient in detecting the pathogenic KIF1A variant responsible for the patient’s clinical symptoms, which they believe will be helpful in saving time and resources for future related diagnoses.
Next-generation sequencing study reveals the broader variant spectrum of hereditary spastic paraplegia and related phenotypes (February 19, 2019)
In efforts to improve diagnostic testing for disorders in the spectrum of hereditary spastic paraplegia, these researchers from Poland used next-generation sequencing to uncover related pathogenic variants in an array of genes, one of which is KIF1A (SPG30).
Polyglutamylation of tubulin’s C-terminal tail controls pausing and motility of kinesin-3 family member KIF1A (February 15, 2019)
With the goal of learning more about the function of the KIF1A gene, Dr. Lessard and team characterized a unique pausing behavior within the microtubule that aids in the KIF1A protein’s ability to transport cargo for long distances within the neuron. This process occurs from C-terminal tail polyglutamylation that reduces KIF1A pausing, giving insight on how the mechanism of KIF1A motility is regulated and the motor’s role in axonal transport.
Kinesin-3 responds to local microtubule dynamics to target synaptic cargo delivery to the presynapse (January 3, 2019)
Led by researchers at the University of Pennsylvania, this paper explores how KIF1A carries on its important function of transporting synaptic vesicles to the synapse and how specific disease-causing mutations on KIF1A affect its molecular behavior and lead to disease.
LITERATURE IN 2018
PEHO syndrome: KIF1A mutation and decreased activity of mitochondrial respiratory chain complex (Samanta, et al)
LITERATURE IN 2017
Autosomal dominant transmission of complicated hereditary spastic paraplegia due to a dominant negative mutation of KIF1A, SPG30 gene (Cheon, et al)
Targeted high throughput sequencing in hereditary ataxia and spastic paraplegia (Iqbal, et al)
Hereditary spastic paraplegia caused by compound heterozygous mutations outside the motor domain of the KIF1A gene. (Krenn, et al)
The KIF1A homolog Unc-104 is important for spontaneous release, postsynaptic density maturation and perisynaptic scaffold organization (Zhang, et al)
Co-existence of spastic paraplegia-30 with novel KIF1A mutation and spinocerebellar ataxia 31 with intronic expansion of BEAN and TK2 in a family. (Hasegawa, et al)
LITERATURE IN 2016
KIF1A inhibition immortalizes brain stem cells but blocks BDNF-mediated neuronal migration (Carabalona, et al)
The Molecular Motor KIF1A Transports the TrkA Neurotrophin Receptor and Is Essential for Sensory Neuron Survival and Function (Tanaka, et al)
Novel De Novo Mutations in KIF1A as a Cause of Hereditary Spastic Paraplegia With Progressive Central Nervous System Involvement (Hotchkiss, et al)
LITERATURE IN 2015
De novo mutations in KIF1A cause progressive encephalopathy and brain atrophy (Nieh, et al)
De novo dominant variants affecting the motor domain of KIF1A are a cause of PEHO syndrome (Langlois, et al)
Variants in KIF1A gene in dominant and sporadic forms of hereditary spastic paraparesis (Citterio, et al)
LITERATURE IN 2011-2014
De Novo Mutations in the Motor Domain of KIF1A Cause Cognitive Impairment, Spastic Paraparesis, Axonal Neuropathy, and Cerebellar Atrophy (Lee, et al)
Motor Protein KIF1A Is Essential for Hippocampal Synaptogenesis and Learning Enhancement in an Enriched Environment (Kondo, et al)
Kinesin-3 Mediates Axonal Sorting and Directional Transport of Alphaherpesvirus Particles in Neurons (Kramer, et al)
Excess of De Novo Deleterious Mutations in Genes Associated with Glutamatergic Systems in Nonsyndromic Intellectual Disability (Hamdan, et al)
Exome sequencing and disease-network analysis of a single family implicate a mutation in KIF1A in hereditary spastic paraparesis. (Erlich, et al)