Alternative titles; symbols
HGNC Approved Gene Symbol: KIF1B
SNOMEDCT: 717016001;
Cytogenetic location: 1p36.22 Genomic coordinates (GRCh38): 1:10,210,570-10,381,603 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p36.22 | {Neuroblastoma, susceptibility to, 1} | 256700 | Autosomal dominant; Somatic mutation | 3 |
| Charcot-Marie-Tooth disease, type 2A1 | 118210 | Autosomal dominant | 3 |
Nangaku et al. (1994) cloned a member of the mouse kinesin superfamily, Kif1b, which encodes an N-terminal-type motor protein. Kif1b was expressed in all tissues tested. In situ hybridization revealed that Kif1b was expressed abundantly in differentiated nerve cells.
Zhao et al. (2001) identified an isoform of mouse Kif1b, which they called Kif1b-beta, that is distinct from Kif1b-alpha (Nangaku et al., 1994) in its cargo-binding domain.
Yang et al. (2001) identified the KIF1B gene in a homozygously deleted region of chromosome 1p36.2 in a neuroblastoma cell line. They reported results suggesting that the gene is not a candidate for tumor suppressor gene of neuroblastoma. Northern blot analysis demonstrated that human KIF1B has at least 2 isoforms. The long isoform (KIF1B-beta) was expressed in a wide variety of tissues, while the short isoform (KIF1B-alpha) was detected only in adult testis.
Schlisio et al. (2008) stated that the KIF1B gene contains 46 coding exons.
By STS analysis, Gong et al. (1996) mapped the human KIF1B gene to chromosome 1p36. They mapped the mouse Kif1b gene to chromosome 4.
Zuchner et al. (2004) stated that the KIF1B gene maps to chromosome 1p36.2, about 1.65 Mb telomeric to the MFN2 gene (608507), which is mutant in Charcot-Marie-Tooth disease type 2A2 (CMT2A2; 609260).
Lawrence et al. (2004) presented a standardized kinesin nomenclature based on 14 family designations. Under this system, KIF1B belongs to the kinesin-3 family.
Nangaku et al. (1994) found that mouse Kif1b works as a monomer, having a microtubule plus-end-directed motility. Rotary shadowing electron microscopy revealed mostly single globular structures. Immunocytochemically, Kif1b was colocalized with mitochondria in vivo. A subcellular fractionation study showed that Kif1b was concentrated in the mitochondrial fraction, and purified Kif1b could transport mitochondria along microtubules in vitro. These data suggested that Kif1b works as a monomeric motor for anterograde transport of mitochondria.
Schlisio et al. (2008) found that apoptosis caused by NGF (see NGFB, 162030) withdrawal from cultured neuronal cells was mediated by EGLN3 (606426) and its downstream effector, KIF1B-beta.
Xu et al. (2018) found that Kif1b -/- mouse hippocampal neurons had significantly impaired axonal outgrowth. Yeast 2-hybrid, immunoprecipitation, and pull-down analyses showed that mouse Kif1b-beta specifically bound mouse Igf1r (147370) to transport it down the neuronal axon. Consequently, Kif1b -/- mouse neuronal axons had decreased surface expression of Igf1r and impaired Igf1 (147440), which correlated with impaired axonal elongation.
Charcot-Marie-Tooth Disease Type 2A1
In all affected members of a family with Charcot-Marie-Tooth disease type 2A1 (CMT2A1; 118210), Zhao et al. (2001) identified a loss-of-function mutation in the KIF1B gene (605995.0001).
Drew et al. (2015) reported a family (family S) in which 2 sisters and a male cousin on the mother's side had weakness of the foot muscles and moderate distal sensory loss and a heterozygous mutation (c.4073T-C, NM_15074.3) in the KIF1B gene. The unaffected mother also carried the mutation, as did all affected and nonpenetrant carrier individuals in the family available for testing. Detailed clinical information and DNA samples for other family members were not available. The authors concluded that the pathogenicity of this variant was questionable.
In affected members of 2 unrelated families with CMT2A1, Xu et al. (2018) identified a heterozygous missense mutation in the KIF1B gene (Y1087C; 605995.0006). The mutation, which was found by exome sequencing, segregated with the disorder in one of the families. In vitro functional expression studies in mouse cells showed that the mutation decreased the binding capacity with Igf1r and impaired the ability of Kif1b to transport Igf1r to the axon. The variant was unable to complement the defects of axonal outgrowth in Kif1b-null mouse primary hippocampal neurons, consistent with a pathogenic effect.
Role in Cancer
In 1 medulloblastoma (155255), 3 neuroblastomas (NBLST1; 256700), and 2 pheochromocytoma (171300) tumor samples, Schlisio et al. (2008) identified 6 different missense mutations in the KIF1B gene. In 3 tumors there was loss of the wildtype allele and in 3 there was retention, including 1 in which there was low-level amplification of the mutant allele. In the 4 cases in which corresponding germline DNA samples from the respective patients were available, the mutations were also present (605995.0002-605995.0005). Functional studies in primary rat sympathetic neurons revealed that induction of apoptosis was impaired with all of the KIF1B variants compared to wildtype.
Associations Pending Confirmation
For discussion of a possible association between variation in the KIF1B gene and multiple sclerosis, see MS4 (612596).
Zhao et al. (2001) generated Kif1b knockout mice by gene targeting. Kif1b knockout mice died at birth from apnea due to nervous system defects. Death of knockout neurons in culture could be rescued by expression of the Kif1b-beta isoform. The Kif1b heterozygotes had a defect in transporting synaptic vesicle precursors and suffered from progressive muscle weakness similar to human neuropathies.
Lyons et al. (2009) identified a mutation in the zebrafish Kif1b gene that disrupted localization of Mbp (159430) mRNA in the central nervous system (CNS) and outgrowth of the posterior lateral line nerve in the peripheral nervous system (PNS). Using antisense morpholino oligonucleotides to block translation of individual Kif1b isoforms, they found that the phenotype was due to loss of Kif1b-beta rather than Kif1b-alpha, even though the mutation occurred in the common region shared by both isoforms. Examination of the zebrafish mutants revealed that Kif1b was required to localize myelin mRNA to oligodendrocyte processes, to elaborate the correct amount of myelin around axons, and to prevent ectopic production of myelin-like membrane. Normal Kif1b function was also required for development of certain axons in the CNS and PNS.
In all affected individuals of a Japanese family (family 694) with autosomal dominant Charcot-Marie-Tooth disease type 2A1 (CMT2A1; 118210) reported by Saito et al. (1997), Zhao et al. (2001) identified an A-to-T transversion in the KIF1B gene, resulting in a gln98-to-leu (Q98L) substitution. The Q98L mutation was not identified in 95 healthy, unrelated Japanese controls. The mutation occurred in the middle of the P loop, the consensus ATP-binding site, and was predicted to disrupt the function of this mechanochemical enzyme. Zhao et al. (2001) tested the motor activity of recombinant mouse Kif1b with the Q98L mutation. The microtubule-activated ATP turnover rates were reduced in the mutant protein. Furthermore, the Q98L mutant protein remained and aggregated in the perinuclear region, while the wildtype Kif1b protein accumulated at the cell periphery. These data suggested that the Q98L mutation resulted in a functional loss of motor activity.
In a neuroblastoma (256700) tumor sample and in germline DNA from the corresponding patient, Schlisio et al. (2008) identified an A-T transversion in exon 20 of the KIF1B gene, resulting in a glu646-to-val (E646V) substitution. There was loss of the wildtype allele in the tumor sample, and MYCN (164840) amplification was present.
In a neuroblastoma (256700) tumor sample and in germline DNA from the corresponding patient, Schlisio et al. (2008) identified a C-T transition in exon 24 of the KIF1B gene, resulting in a thr827-to-ile (T827I) substitution. The wildtype allele was retained in the tumor sample; no amplification of MYCN (164840) was present, but low-level (2-fold) amplification of the mutant allele was detected.
In a neuroblastoma (256700) tumor sample and in germline DNA from the corresponding patient, Schlisio et al. (2008) identified a C-T transition in exon 33 of the KIF1B gene, resulting in a pro1217-to-ser (P1217S) substitution. There was loss of the wildtype allele in the tumor sample, and no MYCN (164840) amplification was present.
In a 28-year-old proband who presented at 17 months of age with a neuroblastoma (256700) and in adulthood developed a mature ganglioneuroma and bilateral pheochromocytoma (171300), Schlisio et al. (2008) identified a 4442G-A transition in exon 41 of the KIF1B gene, resulting in a ser1481-to-asn (S1481N) substitution, in the pheochromocytoma tumor sample and in her germline DNA. The wildtype allele was retained in the tumor sample. Her paternal grandfather harbored the mutant S1481N allele and also developed bilateral pheochromocytoma. In vitro functional expression studies showed that the mutant protein was deficient in the ability to induce apoptosis of sympathetic precursor cells in response to growth factor withdrawal compared to wildtype KIF1B. Yeh et al. (2008) reported further analysis of this family. The proband developed a leiomyosarcoma, and her father, who also carried the S1481N mutation, developed adenocarcinoma of the lung (211980). Analysis of tumor tissue revealed that all 4 neural crest tumors and the leiomyosarcoma retained both KIF1B alleles and showed no loss of heterozygosity (LOH), consistent with a haploinsufficiency mechanism. Yeh et al. (2008) postulated that the leiomyosarcoma may have evolved secondary to the proband's childhood treatment for neuroblastoma. In contrast, about 45% of cells from the lung tumor showed LOH at this locus, suggesting a possible role for gene dosage in development of this nonneural tumor.
In a further study of the family originally reported by Schlisio et al. (2008), Cardot Bauters et al. (2020) found that a brother of the proband, who did not carry the S1481N variant, had developed a bilateral pheochromocytoma and had a heterozygous germline mutation in the MAX gene (154950; c.145T-C, S49P). Loss of the wildtype MAX allele occurred in his pheochromocytoma, suggesting the pathogenicity of the variant. The proband and her grandfather also carried the MAX variant, but no second hit could be found at the somatic level. No other pathogenic mutations in 36 genes predisposing to familial pheochromocytoma/paraganglioma were identified in the proband. The authors concluded that pheochromocytoma in this family was linked to the MAX germline variant and not to the KIF1B germline variant. However, they suggested that the KIF1B variant may have contributed to neuroblastoma in the proband.
In affected members of 2 unrelated families with autosomal dominant Charcot-Marie-Tooth disease type 2A1 (CMT2A1; 118210), Xu et al. (2018) identified a heterozygous c.3260A-G transition in the KIF1B gene, resulting in a tyr1087-to-cys (Y1087C) substitution in the IGF1R binding domain. The mutation, which was found by exome sequencing, segregated with the disorder in one of the families. The variant had a frequency of 0.0395 in the 1000 Genomes Project database. In vitro functional expression studies in mouse cells showed that the mutation decreased the binding capacity with Igf1r and impaired the ability of Kif1b to transport Igf1r to the axon. The variant was unable to complement the defects of axonal outgrowth in Kif1b-null mouse primary hippocampal neurons, consistent with a pathogenic effect.
Cardot Bauters, C., Leteurtre, E., Carnaille, B., Do Cao, C., Espiard, S., Penven, M., Destailleur, E., Szuster, I., Lovecchio, T., Leclerc, J., Frenois, F., Esquivel, E., Dahia, P. L. M., Ait-Yahya, E., Crepin, M., Pigny, P. Genetic predisposition to neural crest-derived tumors: revisiting the role of KIF1B. Endocr. Connect. 9: 1042-1050, 2020. [PubMed: 33112832] [Full Text: https://doi.org/10.1530/EC-20-0460]
Drew, A. P., Zhu, D., Kidambi, A., Ly, C., Tey, S., Brewer, M. H., Ahmad-Annuar, A., Nicholson, G. A., Kennersen, M. L. Improved inherited peripheral neuropathy genetic diagnosis by whole-exome sequencing. Molec. Genet. Genomic Med. 3: 143-154, 2015. [PubMed: 25802885] [Full Text: https://doi.org/10.1002/mgg3.126]
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Lyons, D. A., Naylor, S. G., Scholze, A., Talbot, W. S. Kif1b is essential for mRNA localization in oligodendrocytes and development of myelinated axons. Nature Genet. 41: 854-858, 2009. [PubMed: 19503091] [Full Text: https://doi.org/10.1038/ng.376]
Nangaku, M., Sato-Yoshitake, R., Okada, Y., Noda, Y., Takemura, R., Yamazaki, H., Hirokawa, N. KIF1B, a novel microtubule plus end-directed monomeric motor protein for transport of mitochondria. Cell 79: 1209-1220, 1994. [PubMed: 7528108] [Full Text: https://doi.org/10.1016/0092-8674(94)90012-4]
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Xu, F., Takahashi, H., Tanaka, Y., Ichinose, S., Niwa, S., Wicklund, M. P., Hirokawa, N. KIF1B-beta mutations detected in hereditary neuropathy impair IGF1R transport and axon growth. J. Cell Biol. 217: 3480-3496, 2018. [PubMed: 30126838] [Full Text: https://doi.org/10.1083/jcb.201801085]
Yang, H. W., Chen, Y. Z., Takita, J., Soeda, E., Piao, H. Y., Hayashi, Y. Genomic structure and mutational analysis of the human KIF1B gene which is homozygously deleted in neuroblastoma at chromosome 1p36.2. Oncogene 20: 5075-5083, 2001. [PubMed: 11526494] [Full Text: https://doi.org/10.1038/sj.onc.1204456]
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Zhao, C., Takita, J., Tanaka, Y., Setou, M., Nakagawa, T., Takeda, S., Yang, H. W., Terada, S., Nakata, T., Takei, Y., Saito, M., Tsuji, S., Hayashi, Y., Hirokawa, N. Charcot-Marie-Tooth disease type 2A caused by mutation in a microtubule motor KIF1B-beta. Cell 105: 587-597, 2001. Note: Erratum: Cell 106: 127 only, 2001. [PubMed: 11389829] [Full Text: https://doi.org/10.1016/s0092-8674(01)00363-4]
Zuchner, S., Mersiyanova, I. V., Muglia, M., Bissar-Tadmouri, N., Rochelle, J., Dadali, E. L., Zappia, M., Nelis, E., Patitucci, A., Senderek, J., Parman, Y., Evgrafov, O., and 10 others. Mutations in the mitochondrial GTPase mitofusin 2 cause Charcot-Marie-Tooth neuropathy type 2A. Nature Genet. 36: 449-451, 2004. Note: Erratum: Nature Genet. 36: 660 only, 2004. [PubMed: 15064763] [Full Text: https://doi.org/10.1038/ng1341]