We firmly believe every family should have access to critical scientific data about KIF1A. To take a more active role in advancing KIF1A research, we encourage all KAND families to participate in the ongoing Natural History Study, which records and compares known cases of KIF1A Associated Neurological Disorder (KAND). This study is vital to understanding KAND and swiftly developing strategies for treatment.
Visit our Completed Studies page for information on studies prior to 2019.
RECENT RESEARCH STUDIES
The following publications reflect key KIF1A-related studies that are ongoing or completed after 2018. Check out our Research Simplified articles to see summaries of significant research, written by researchers for KIF1A families. For additional KIF1A papers, visit the Completed Studies page or view KIF1A research in PubMed.gov.
Through our Research Simplified category on the blog, scientists are given the opportunity to explain their publications to the KIF1A.ORG community. If the abstracts and full research publications leave you scratching your head, these simple overviews of research studies and their findings are a great place to start on your journey to learning more about KIF1A and KAND.
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 (Apr 30th, 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 (Apr 8th, 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 (Feb 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 (Feb 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 (Jan 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 (Jan 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 (Nov 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 (Oct 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 (Oct 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 (Sept 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 (Aug 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 (Jun 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 (Apr 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 (Feb, 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 (Feb 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 (Feb 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 (Jan 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 (Dec 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 (Dec 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 (Dec 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 (Nov 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 (Oct 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 (Sept 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 (Sept 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 (Sept 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 (Jul 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 (Mar 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 (Feb 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 (Feb 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 (Jan 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.