Alternative titles; symbols
HGNC Approved Gene Symbol: KIF1A
SNOMEDCT: 763377006;
Cytogenetic location: 2q37.3 Genomic coordinates (GRCh38): 2:240,713,767-240,821,403 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q37.3 | NESCAV syndrome | 614255 | Autosomal dominant | 3 |
| Neuropathy, hereditary sensory, type IIC | 614213 | Autosomal recessive | 3 | |
| Spastic paraplegia 30, autosomal dominant | 610357 | Autosomal dominant; Autosomal recessive | 3 | |
| Spastic paraplegia 30, autosomal recessive | 610357 | Autosomal dominant; Autosomal recessive | 3 |
The KIF1A gene encodes a motor protein involved in the anterograde transport of synaptic-vesicle (SV) precursors along axons (summary by Riviere et al., 2011).
In a search for candidate genes for the tuberous sclerosis-1 (TSC1; 191100) disease locus, Furlong et al. (1996) identified a novel gene, the axonal transporter of synaptic vesicles (ATSV) gene, that maps adjacent to a CpG island, approximately 80 kb centromeric of the ABO (110300) locus on chromosome 9q34.1-q34.2. (The ATSV gene was later mapped to chromosome 2q37; see 'Mapping,' below.) Furlong et al. (1996) obtained 7 kb of continuous sequence from a series of overlapping cosmid clones and corresponding cDNA clones which were isolated from a brain cDNA library. Sequence analysis revealed an open reading frame of 5,070 bp encoding a putative protein which shows 97% identity at the amino acid level to the mouse KIF1A gene product and 42% identity with the C. elegans unc-104 genes. Both KIF1A and unc-104 function in the anterograde axonal transport of synaptic vesicles and are members of the kinesin gene family (see 600025). The ATSV gene is transcribed in the direction 9qter to 9cen. A CpG island was found at the 3-prime end of the gene. The ATSV gene probes detected a NotI polymorphism which occurred with a frequency of 2%. Furlong et al. (1996) found no supporting evidence for ATSV as the candidate TSC1 gene.
Lawrence et al. (2004) presented a standardized kinesin nomenclature based on 14 family designations. Under this system, KIF1A belongs to the kinesin-3 family.
Kinesin-related proteins constitute a large superfamily of microtubule-dependent proteins that mediate specific and diverse motile processes, including intracellular transport and cell division. The human ATSV protein is a member of the kinesin family and shows 95% identity to the KIF1A protein of mouse (Okada et al., 1995). KIF1A is an anterograde motor protein that transports membranous organelles along axonal microtubules. Its cargo includes a subset of precursors for synaptic vesicles: synaptophysin (313475), synaptotagmin (185605), and Rab3A (179490). The phenotype of KIF1A knockout mice includes motor and sensory disturbances, a reduction in the density of synaptic vesicles in nerve terminals, and accumulation of clear vesicles in nerve cell bodies (Yonekawa et al., 1998). It can be hypothesized that ATSV (and KIF1A in the mouse) may play a critical role in the development of axonal neuropathies resulting from impaired axonal transport.
Using an in vitro motility assay, Klopfenstein et al. (2002) showed that Dictyostelium Unc104 uses a lipid-binding pleckstrin homology (PH) domain to dock onto membrane cargo. Through its PH domain, Unc104 could transport phosphatidylinositol(4,5)bisphosphate (PtdIns(4,5)P2)-containing liposomes with similar properties to native vesicles. Liposome movement by monomeric Unc104 motors showed a steep dependence on PtdIns(4,5)P2 concentration, even though liposome binding was noncooperative. This switch-like transition for movement could be shifted to lower PtdIns(4,5)P2 concentrations by the addition of cholesterol/sphingomyelin or GM1 ganglioside/cholera toxin, conditions that produced raft-like behavior of Unc104 bound to lipid bilayers. The authors concluded that clustering of Unc104 in PtdIns(4,5)P2-containing rafts provides a trigger for membrane transport.
Tomishige et al. (2002) demonstrated that KIF1A can dimerize and move unidirectionally and processively with rapid velocities characteristic of transport in living cells. Their results suggested that KIF1A operates in vivo by a mechanism similar to conventional kinesin and that regulation of motor dimerization may be used to control transport by this class of kinesins.
In a yeast 2-hybrid screen using a human fetal brain cDNA library, Riviere et al. (2011) found that the KIF1A gene interacted with the HSN2 exon of WNK1 (605232). Immunoprecipitation studies showed that the 2 proteins localized in cultured primary sensory neurons prepared from adult mouse dorsal root ganglia. Both proteins were found to localize in cell bodies and along axons, suggesting a role in axonal transport.
Using a mass spectrometry approach, Stucchi et al. (2018) identified TANC2 (615047), liprin-alpha-2 (PPFIA2; 603143), and the calcium-binding protein calmodulin (see CALM1, 114180) as direct binding partners of KIF1A, the primary motor protein for SVs and dense core vesicles (DCVs). Analysis with rat hippocampal neurons revealed that calcium enhanced Kif1a binding to DCVs and increased vesicle motility by acting through calmodulin. Tanc2 and liprin-alpha-2 were enriched in dendritic spines but were not part of the Kif1a cargo complex. Instead, they acted as postsynaptic density scaffolds to stop and capture Kif1a-bound DCVs upon dendritic spine entry. Knockdown experiments showed that depletion of Tanc2, Kif1a, or liprin-alpha-2 affected rat dendritic spine density and morphology.
X-Ray Crystallography and Cryoelectron Microscopy
Kikkawa et al. (2000) generated a 15-angstrom resolution map of the KIF1A-microtubule complex, which allowed clear visualization of the K loop, a 12-amino acid insert in the L12 region, as an arm-like structure. Furthermore, this high-resolution model revealed how kinesin motors interact with microtubules. KIF1A has 3 microtubule-binding sites, termed MB1, MB2, and MB3. MB3 is the unique arm-like projection containing the K loop.
Kikkawa et al. (2001) studied the monomeric kinesin motor KIF1A using x-ray crystallography and cryoelectron microscopy, to allow analysis of force-generating conformational changes at atomic resolution. Their analysis revealed the motor in its 2 functionally critical states, complexed with ADP and with a nonhydrolyzable analog of ATP. The conformational change observed between the 2 structures of the KIF1A catalytic core is modular, extends to all kinesins, and is similar to the conformational change used by myosin motors and G proteins. Docking of the ADP-bound and ATP-like crystallographic models of KIF1A into the corresponding cryoelectron microscopy maps suggests a rationale for the plus-end directional bias associated with the kinesin catalytic core.
Nitta et al. (2004) reported crystal structures of monomeric kinesin KIF1A with 3 transition-state analogs: adenylyl imidodiphosphate (AMP-PNP), adenosine diphosphate (ADP)-vanadate, and ADP-AlFx (aluminofluoride complexes). These structures, together with known structures of the ADP-bound state and the adenylyl-(beta,gamma-methylene) diphosphate (AMP-PCP)-bound state, show that kinesin uses 2 microtubule-binding loops in an alternating manner to change its interaction with microtubules during the ATP hydrolysis cycle; loop L11 is extended into the AMP-PNP structure, whereas loop L12 is extended in the ADP structure. ADP-vanadate displays an intermediate structure in which a conformational change in 2 switch regions causes both loops to be raised from the microtubule, thus actively detaching kinesin.
Optical Trapping
By measuring its movement with an optical trapping system, Okada et al. (2003) used KIF1A as a model molecule to demonstrate that a single ATP hydrolysis triggers a single stepping movement of a single KIF1A monomer. The step size is distributed stochastically around multiples of 8 nm with a gaussian-like envelope and a standard deviation of 15 nm. On average, the step is directional to the microtubule's plus-end against a load force of up to 0.15 pN. As the source for this directional movement, Okada et al. (2003) showed that KIF1A moves to the microtubule's plus-end by approximately 3 nm on average on binding to the microtubule, presumably by preferential binding to tubulin on the plus-end side.
Amyotrophic lateral sclerosis-4 (ALS4; 602433) is an autosomal dominant, juvenile-onset motor systems disease with an axonal phenotype that includes prominent axonal swelling. The ALS4 locus maps to 9q34, a region that overlaps the putative ATSV gene region, making it an attractive positional and functional candidate gene for ALS4. Keller et al. (1999) investigated the ATSV gene as a candidate gene for ALS4 and failed to confirm the assignment of the ATSV gene to chromosome 9. By PCR analysis of a human/rodent somatic cell hybrid panel and by FISH, they instead mapped the human ATSV gene to 2q37. The ATSV gene therefore becomes a candidate gene for other peripheral nerve disorders involving altered axonal transport mapping to 2q37. Keller et al. (1999) suggested that a limited stretch of sequence identity to the ATSV transcript in the previously identified region of 9q34 may have led to the prior conclusion that the ATSV gene maps to chromosome 9. Alternatively, a chimerism in the YAC clone used to generate the cosmid in that previous study may have led to the erroneous mapping of the ATSV gene to 9q34.
Spastic Paraplegia 30, Autosomal Dominant
In a father and son of Finnish descent with pure autosomal dominant spastic paraplegia-30 (SPG30; 610357), Ylikallio et al. (2015) identified a heterozygous mutation (S69L; 601255.0014) in the KIF1A gene; the substitution affected a moderately conserved residue in the motor domain. The mutation, which was found by targeted next-generation sequencing and confirmed by Sanger sequencing, was demonstrated to have occurred de novo in the father. The variant was not present in the 1000 Genomes Project or Exome Variant Server databases. Functional studies of the variant and studies of patient cells were not performed.
In 4 affected members of a multigenerational Sicilian family with autosomal dominant SPG30, Citterio et al. (2015) identified a heterozygous S69L mutation in the KIF1A gene. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the ExAC database. Functional studies of the variant and studies of patient cells were not performed.
In 3 members of a 3-generational family with SPG30, Roda et al. (2017) identified a heterozygous S69L mutation in the KIF1A gene. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not present in the ExAC database. Functional studies of the variant and studies of patient cells were not performed.
In 4 patients (patients 6, 8A, 8B, and 9), including 2 sibs, with SPG30, Nemani et al. (2020) identified heterozygous mutations in the KIF1A gene. Three patients carried the S69L mutation, whereas 1 had an R11Q mutation. Functional studies of the variants were not performed.
In 23 probands with SPG30, Pennings et al. (2020) identified 19 different heterozygous point mutations in the KIF1A gene. There were 11 missense variants in the motor domain (see, e.g., S69L, 601255.0014), as well as 9 variants outside of the motor domain. Six of these 9 mutations were nonsense or frameshift mutations (see, e.g., 601255.0015 and 601255.0016) predicted to result in a loss of function. Three variants were considered to be 'variants of unknown significance'. Functional studies of the variants and studies of patient cells were not performed. The findings suggested that autosomal dominant SPG30 can be caused by either missense or loss-of-function mutations. The patients were ascertained from a cohort of 347 probands with SPG who underwent exome sequencing.
Spastic Paraplegia 30, Autosomal Recessive
By homozygosity mapping, exome sequencing, and examination of candidate genes, Erlich et al. (2011) identified a homozygous mutation in the KIF1A gene (A255V; 601255.0001) in 3 Palestinian sibs with autosomal recessive spastic paraplegia-30 (SPG30; see 610357).
Klebe et al. (2012) identified a homozygous mutation in the KIF1A gene (R350G; 601255.0005) in affected members of a consanguineous Algerian family with SPG30 originally reported by Klebe et al. (2006). Another Palestinian family with the disorder was found to be homozygous for the A255V mutation.
Functional Studies of SPG30-Associated KIF1A Mutations
Using in vitro motility assays and rescue experiments in C. elegans, Chiba et al. (2019) showed that some SPG30-associated mutations in human KIF1A, including A255V and R350G, hyperactivated KIF1A rather than causing loss of function. Introduction of the corresponding mutations in C. elegans Unc104 led to abnormal accumulation of synaptic vesicle precursors (SVPs) at the tips of axons and increased anterograde axonal transport of SVPs. The authors concluded that hyperactivation of kinesin motor activity can cause motor neuron disease in humans.
Hereditary Sensory Neuropathy, Type IIC
By genomewide homozygosity mapping followed by candidate gene analysis in a consanguineous Afghan family with hereditary sensory neuropathy type IIC (HSN2C; 614213), Riviere et al. (2011) identified a homozygous truncating mutation in the KIF1A gene (601255.0002). Screening of this gene in 112 unrelated patients with HSN identified 2 additional families with the same mutation and 1 patient who was compound heterozygous for 2 mutations (601255.0002 and 601255.0003).
NESCAV Syndrome
In a patient with NESCAV syndrome (NESCAVS; 614255), Hamdan et al. (2011) identified a missense mutation (T99M; 601255.0004) in the KIF1A gene. The mutation affected localization of the KIF1A protein in neurites.
In 14 patients, including a pair of monozygotic twins, with NESCAVS, Lee et al. (2015) identified 11 different de novo heterozygous missense mutations in the KIF1A gene (see, e.g., 601255.0004, 601255.0006-601255.0008). The mutations in 12 families were found by exome sequencing; the mutation in 1 family was found by targeted next-generation sequencing. All the mutations occurred at conserved residues in the motor domain. In vitro functional expression studies of 5 of the mutations in rat hippocampal cells showed that they resulted in greatly reduced distal localization in neurites compared to wildtype. The patients had intellectual disability with variable cerebellar atrophy, spastic paraparesis, optic atrophy, peripheral neuropathy, and seizures. Lee et al. (2015) hypothesized that, since KIF1A functions as an active dimer, heterozygous missense mutations may exert a dominant-negative effect, which may explain the severe phenotype compared to those with recessive mutations.
In 6 unrelated patients with NESCAVS, Esmaeeli Nieh et al. (2015) identified 5 different de novo heterozygous missense mutations in the KIF1A gene (see, e.g., 601255.0004, 601255.0007, 601255.0009-601255.0010). The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. All mutations occurred at conserved residues in the motor domain, and in vitro functional microtubule gliding assays of several of the mutations showed that they resulted in a loss of motility with evidence for a dominant-negative effect. The patients had a severe neurodegenerative encephalopathy, with progressive cerebral and cerebellar atrophy, thus expanding the phenotype associated with de novo KIF1A mutations.
In 5 unrelated patients with NESCAVS, Ohba et al. (2015) identified 5 different de novo heterozygous missense mutations in the KIF1A gene (see, e.g., 601255.0011 and 601255.0012). All of the mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, affected highly conserved residues in the motor domain. Functional studies of the variants and studies of patient cells were not performed, but molecular modeling predicted that the variants would destabilize the protein or affect protein function.
In 2 unrelated patients with NESCAVS, Hotchkiss et al. (2016) identified 2 de novo heterozygous missense mutations in the KIF1A gene (see, e.g., G199R, 601255.0013). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, were not found in multiple public databases, including dbSNP, the Exome Variant Server, and ExAC. Functional studies of the variants and studies of patient cells were not performed, but both occurred in the motor domain and were predicted to interfere with microtubule binding, possibly with a dominant-negative effect.
In 2 unrelated patients with NESCAVS, Van Beusichem et al. (2020) identified de novo heterozygous missense variants in the KIF1A gene (R380W; R216C, 601255.0009). Functional studies of the variants and studies of patient cells were not performed. In a review of previously reported cases, the authors concluded that there is no apparent genotype/phenotype correlation.
In a 4-year-old girl with NESCAVS who presented with clinical features of PEHO and a mitochondrial disorder, Samanta and Gokden (2019) identified a de novo heterozygous E253K mutation in the KIF1A gene (601255.0007). The mutation was found by whole-exome sequencing. Functional studies of the variant were not performed.
In 8 patients with NESCAVS, Nemani et al. (2020) identified de novo heterozygous mutations in the KIF1A gene (see, e.g., R254W, 601255.0012 and R307P, 601255.0017). All except 1 were missense variants affecting the kinesin motor domain; 1 was a splice site mutation. Two patients with profound encephalopathy carried the heterozygous E253K mutation. Functional studies of the variants were not performed.
Klebe et al. (2012) observed that patients with truncating mutations in the KIF1A gene (see, e.g., 601255.0002) tended to present with a peripheral nervous system disorder (HSN2C), whereas those with missense mutations (see, e.g., 601255.0001) tended to present with an upper motor neuron syndrome of the central nervous system (SPG30). However, some patients with central nervous system spasticity also developed dysfunction of the peripheral nervous system, and only a few families with KIF1A mutations had been reported by that time.
Yonekawa et al. (1998) found that Kif1a-null mice died within several days after birth and showed severe motor and sensory disturbances, including ataxia, abnormal limb movements, and diminished pain response. Analysis of spinal cord cells and axons showed decreased densities of nerve terminals and synaptic vesicles in the nerve terminals and abnormal clustering of small vesicles in nerve cell bodies, suggesting a defect in anterograde axonal transport. Mutant mice also showed significant neuronal and axonal degeneration and death, and neuronal degeneration and death also occurred in cultures of mutant neurons. The neuronal death in cultures was blocked by coculture with wildtype neurons or exposure to a low concentration of glutamate, suggesting that the neuronal death was due to lack of afferent stimulation resulting from lack of synaptic transmission. The findings indicated that Kif1a transports synaptic vesicle precursors and that this action plays a critical role in viability, maintenance, and function of neurons.
In 3 Palestinian sibs with autosomal recessive spastic paraplegia-30 (SPG30; see 610357), Erlich et al. (2011) identified a homozygous mutation in the KIF1A gene, resulting in an ala255-to-val (A255V) substitution in a highly conserved residue in the motor domain. Each unaffected parent was heterozygous for the mutation, which was found in 3 of 573 individuals from the same ethnic origin, yielding a carrier frequency of 1:191 in this population. The patients had early childhood onset of pure spasticity and hyperreflexia affecting the lower limbs; sensation was intact.
Klebe et al. (2012) identified a homozygous A255V mutation in affected members of a consanguineous Palestinian family with SPG30. Age at onset ranged from 10 to 39 years, and patients had spastic gait with axonal sensorineuropathy after long disease duration. None had cerebellar signs.
In rat hippocampal neurons, Lee et al. (2015) found that the A255V mutation resulted in mildly decreased distal localization in neurites (80.8% compared to wildtype).
In an in vitro microtubule gliding assay, Esmaeeli Nieh et al. (2015) showed that the mutant A255V protein had motility similar to wildtype.
Using in vitro motility assays and rescue experiments in C. elegans, Chiba et al. (2019) showed that some SPG30-associated mutations in human KIF1A, including A255V, hyperactivated KIF1A rather than causing loss of function. Introduction of the corresponding mutation in C. elegans Unc104 led to abnormal accumulation of synaptic vesicle precursors (SVPs) at the tips of axons and increased anterograde axonal transport of SVPs.
In affected members of 3 unrelated families with hereditary sensory neuropathy IIC (HSN2C; 614213), Riviere et al. (2011) identified a homozygous 1-bp deletion (2840delT) in the alternatively spliced exon 25b of the KIF1A gene, predicted to cause a frameshift (Leu947Argfs*4). The mutation was not found in 665 European controls. One of the families was Afghan, 1 was Turkish, and 1 was Belgian; 2 of the families were consanguineous. Another Belgian patient, with a more severe disorder, was compound heterozygous for 2840delT and a 1-bp insertion (5271dupC; 601255.0003) in exon 46, predicted to cause a frameshift and premature termination (Ser1758GlnfsTer7).
For discussion of the 1-bp duplication in exon 46 of the KIF1A gene (5271dupC) that was found in compound heterozygous state in a patient with hereditary sensory neuropathy IIC (HSN2C; 614213) by Riviere et al., 2011, see 601255.0002.
In a 3.5-year-old girl (patient 7) with NESCAV syndrome (NESCAVS; 614255), Hamdan et al. (2011) identified a heterozygous C-to-T transition at nucleotide 296 of the KIF1A gene, resulting in a thr-to-met substitution at codon 99 (T99M). The patient also had axial hypotonia with peripheral spasticity, and mild atrophy of the vermian region of the cerebellum on MRI. This mutation was not identified in the patient's parents or in 285 control chromosomes. Functional assays showed that the mutation affected the localization of KIF1A from distal regions of neurites, as seen in wildtype, to reduced distal localization and increased accumulation throughout the cell body and proximal neurites in cells transfected with a mutant protein.
Lee et al. (2015) identified a de novo heterozygous T99M mutation (c.296C-T, NM_001244008.1) in 2 unrelated girls (patients 1 and 2) with NESCAVS. The mutation occurred at a conserved residue in the nucleotide-binding pocket in the motor domain and was predicted to abolish the interaction of KIF1A with the gamma-phosphate of ATP. In vitro functional expression studies in rat hippocampal cells showed that the mutation resulted in greatly reduced distal localization in neurites (15.9% compared to wildtype). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the dbSNP (build 138), 1000 Genomes Project, or Exome Variant Server databases or in over 5,500 in-house control exomes.
Esmaeeli Nieh et al. (2015) identified a de novo heterozygous T99M mutation in 2 unrelated patients (patients 1 and 2) with NESCAVS. An in vitro microtubule gliding assay showed that the mutant protein had no motility.
Okamoto et al. (2014) and Langlois et al. (2016) identified de novo heterozygous T99M mutations in 2 unrelated patients with NESCAVS. The mutations were found by exome sequencing and confirmed by Sanger sequencing. Functional studies of the variant and studies of patient cells were not performed, but the findings further suggested that a severe phenotype is associated with this mutation. Okamoto et al. (2014) speculated that since the KIF1A protein homodimerizes, the T99M mutation may cause a dominant-negative effect.
In 4 sibs, born of consanguineous Algerian parents, with autosomal recessive spastic paraplegia-30 (SPG30; see 610357), who were originally reported by Klebe et al. (2006), Klebe et al. (2012) identified a homozygous 1048C-G transversion in exon 13 of the KIF1A gene, resulting in an arg350-to-gly (R350G) substitution at a highly conserved residue in the motor domain. Each unaffected parent was heterozygous for the mutation, which was not found in 970 control chromosomes. The mutation occurred at the end of the motor domain in close vicinity to the neck linker that has an important role in directionality. Affected individuals had spasticity, sensorimotor axonal neuropathy, and mild cerebellar signs.
In rat hippocampal neurons, Lee et al. (2015) found that the R350G mutation resulted in greatly reduced distal localization in neurites (20.7% compared to wildtype).
Using in vitro motility assays and rescue experiments in C. elegans, Chiba et al. (2019) showed that some SPG30-associated mutations in human KIF1A, including R350G, hyperactivated KIF1A rather than causing loss of function. Introduction of the corresponding human mutation in C. elegans Unc104 led to abnormal accumulation of synaptic vesicle precursors (SVPs) at the tips of axons and increased anterograde axonal transport of SVPs.
In a 4-year-old boy (patient 6) with NESCAV syndrome (NESCAVS; 614255), Lee et al. (2015) identified a de novo heterozygous c.643A-C transversion (c.643A-C, NM_001244008.1) in the KIF1A gene, resulting in a ser215-to-arg (S215R) substitution at a conserved residue in the nucleotide-binding pocket in the motor domain. Structural modeling predicted that the mutation would abolish the interaction of KIF1A with the gamma-phosphate of ATP. In vitro functional expression studies in rat hippocampal cells showed that the mutation resulted in greatly reduced distal localization in neurites (13.5% compared to wildtype). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the dbSNP (build 138), 1000 Genomes Project, or Exome Variant Server databases or in over 5,500 in-house control exomes.
In 2 unrelated girls (patients 8 and 9) with NESCAV syndrome (NESCAVS; 614255), Lee et al. (2015) identified a de novo heterozygous c.757G-A transition (c.757G-A, NM_001244008.1) in the KIF1A gene, resulting in a glu253-to-lys (E253K) substitution at a conserved salt bridge-forming residue in the motor domain. Structural modeling predicted that the mutation would disrupt this structure, suppress ATP gamma-phosphate release, and prevent additional ATP binding. In vitro functional expression studies in rat hippocampal cells showed that the mutation resulted in greatly reduced distal localization in neurites (19.3% compared to wildtype). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the dbSNP (build 138), 1000 Genomes Project, or Exome Variant Server databases or in over 5,500 in-house control exomes. Both girls had a severe phenotype with optic atrophy and cerebral and cerebellar atrophy, resulting in death before age 4 years.
Esmaeeli Nieh et al. (2015) identified a de novo heterozygous E253K mutation in a patient with NESCAVS. An in vitro microtubule gliding assay showed that the mutant protein had no motility and acted in a dominant-negative manner.
In a 4-year-old girl with NESCAVS who presented with clinical features of PEHO and a mitochondrial disorder, Samanta and Gokden (2019) identified a de novo heterozygous E253K mutation in the KIF1A gene. The mutation was found by whole-exome sequencing. Functional studies of the variant were not performed.
Nemani et al. (2020) identified de novo heterozygous E253K mutations in 2 unrelated infants (patients 1 and 2) with a severe form of NESCAV syndrome. Functional studies were not performed.
In a 30-month-old girl (patient 5) with NESCAV syndrome (NESCAVS; 614255), Lee et al. (2015) identified a de novo heterozygous c.604G-C transversion (c.604G-C, NM_001244008.1) in the KIF1A gene, resulting in an ala202-to-pro (A202P) substitution near a conserved salt bridge-forming residue in the motor domain. Structural modeling predicted that the mutation would induce a conformational change, likely disrupting efficient ATP gamma-phosphate release and additional ATP binding. In vitro functional expression studies in rat hippocampal cells showed that the mutation resulted in greatly reduced distal localization in neurites (9.9% compared to wildtype). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the dbSNP (build 138), 1000 Genomes Project, or Exome Variant Server databases or in over 5,500 in-house control exomes.
In a 2-year-old girl (patient 3) with NESCAV syndrome (NESCAVS; 614255), Esmaeeli Nieh et al. (2015) identified a de novo heterozygous c.646C-T transition (c.646C-T, NM_001244008) in the KIF1A gene, resulting in an arg216-to-cys (R216C) substitution at a highly conserved residue in the motor domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was filtered against the dbSNP (build 137), 1000 Genomes Project, and Exome Sequencing Project (ESP6500) databases. An in vitro microtubule gliding assay showed that the mutant protein had no motility.
Van Beusichem et al. (2020) identified a de novo R216C mutation in a 15-year-old girl (patient 4) with NESCAVS. She did not have optic nerve atrophy or seizures, but showed cerebellar atrophy on brain imaging. Functional studies of the variant were not performed.
In a 16-year-old boy (patient 5) with NESCAV syndrome (NESCAVS; 614255), Esmaeeli Nieh et al. (2015) identified a de novo heterozygous c.647G-A transition (c.647G-A, NM_001244008) in the KIF1A gene, resulting in an arg216-to-his (R216H) substitution at a highly conserved residue in the motor domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was filtered against the dbSNP (build 137), 1000 Genomes Project, and Exome Sequencing Project (ESP6500) databases. Functional studies of this variant were not performed, but an in vitro microtubule gliding assay of a mutation at the same residue (R216C; 601255.0009) showed that the R216C mutant protein had no motility. This patient also carried a missense variant of unknown significance in the NID1 gene (T408K; 131390), which may have explained his cataracts.
In an 8-year-old boy (patient 1) with NESCAV syndrome (NESCAVS; 614255), Ohba et al. (2015) identified a de novo heterozygous c.761G-A transition (c.761G-A, NM_001244008.1) in the KIF1A gene, resulting in an arg254-to-gln (R254Q) substitution at a conserved residue in the motor domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the dbSNP (build 138), Exome Sequencing Project, 1000 Genomes Project, or ExAC databases, or in an in-house database of 575 control exomes. Functional studies of the variant and studies of patient cells were not performed.
In a 27-year-old woman (patient 2) with NESCAV syndrome (NESCAVS; 614255), Ohba et al. (2015) identified a de novo heterozygous c.760C-T transition (c.760C-T, NM_001224008.1) in the KIF1A gene, resulting in an arg254-to-trp (R254W) substitution at a conserved residue in the motor domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the dbSNP (build 138), Exome Sequencing Project, 1000 Genomes Project, or ExAC databases, or in an in-house database of 575 control exomes. Functional studies of the variant and studies of patient cells were not performed.
In a 6-year-old Brazilian boy (patient 2) with NESCAV syndrome (NESCAVS; 614255), Hotchkiss et al. (2016) identified a de novo heterozygous c.595G-A transition in the KIF1A gene, resulting in a gly199-to-arg (G199R) substitution at a conserved residue in the motor domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in multiple public databases, including dbSNP, the Exome Variant Server, and ExAC. Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to interfere with microtubule binding, possibly with a dominant-negative effect.
In a father and son of Finnish descent with pure autosomal dominant spastic paraplegia-30 (SPG30; 610357), Ylikallio et al. (2015) identified a heterozygous c.206C-T transition (c.206C-T, NM_001244008.1) in the KIF1A gene, resulting in a ser69-to-leu (S69L) substitution at a moderately conserved residue in the motor domain. The mutation, which was found by targeted next-generation sequencing and confirmed by Sanger sequencing, was demonstrated to have occurred de novo in the father. The variant was not present in the 1000 Genomes Project or Exome Variant Server databases. Functional studies of the variant and studies of patient cells were not performed.
In 4 affected members of a multigenerational Sicilian family with autosomal dominant SPG30, Citterio et al. (2015) identified a heterozygous S69L mutation in the KIF1A gene. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the ExAC database. Functional studies of the variant and studies of patient cells were not performed.
In 3 members of a 3-generation family with autosomal dominant SPG30, Roda et al. (2017) identified a heterozygous S69L mutation in the KIF1A gene. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the ExAC database. Functional studies of the variant and studies of patient cells were not performed.
Pennings et al. (2020) identified a heterozygous S69L mutation in 3 members of a multigenerational family (P3) with SPG30. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the gnomAD database. Functional studies of the variant were not performed.
In a father and daughter (family P16) with autosomal dominant spastic paraplegia-30 (SPG30; 610357), Pennings et al. (2020) identified a heterozygous c.1867C-T transition (c.1867C-T, NM_001244008.1) in the KIF1A gene, resulting in a gln623-to-ter (Q623X) substitution. The mutation, which was found by exome sequencing, was not found in the gnomAD database. The nonsense mutation occurred outside of the motor domain and was predicted to result in a loss of function. However, functional studies of the variant and studies of patient cells were not performed.
In a father and his 2 daughters (family P20) with autosomal dominant spastic paraplegia-30 (SPG30; 610357), Pennings et al. (2020) identified a heterozygous c.3975C-G transversion in the KIF1A gene, resulting in a tyr1325-to-ter (Y1325X) substitution. The mutation, which was found by exome sequencing, was not found in the gnomAD database. The nonsense mutation occurred outside of the motor domain and was predicted to result in a loss of function. However, functional studies of the variant and studies of patient cells were not performed.
In a pair of monozygotic twin sisters (patients 5A and 5B) with NESCAV syndrome (NESCAVS; 614255), Nemani et al. (2020) identified a de novo heterozygous c.920G-C transversion (c.920G-C, NM_004321.6) in the KIF1A gene, resulting in an arg307-to-pro (R307P) substitution in the motor domain. Functional studies of the variant and studies of patient cells were not performed.
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