Alternative titles; symbols
HGNC Approved Gene Symbol: KIF3B
Cytogenetic location: 20q11.21 Genomic coordinates (GRCh38): 20:32,277,651-32,335,011 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 20q11.21 | Retinitis pigmentosa 89 | 618955 | Autosomal dominant | 3 |
In eukaryotic cells, proteins and lipids are sorted and transported to their correct destinations at distinct velocities by each organelle or protein complex. Kinesin superfamily proteins are a molecular motor superfamily involved in these processes, conveying their own cargoes along microtubules. Nagase et al. (1997) cloned the KIF3B gene, which they referred to as KIAA0359, the human homolog of the mouse kinase superfamily 3B gene (Yamazaki et al., 1995). The human KIF3B gene encodes a 747-amino acid protein that shares 98% identity with the mouse Kif3b protein. RT-PCR analysis revealed that the KIF3B gene was ubiquitously expressed in all human tissues tested.
By analysis of radiation hybrid panels, Nagase et al. (1997) mapped the KIF3B gene to chromosome 20. Gross (2012) mapped the KIF3B gene to chromosome 20q11.21 based on an alignment of the KIF3B sequence (GenBank BC136310) with the genomic sequence (GRCh37).
Using immunoprecipitation analysis, Alsabban et al. (2020) found that Kif3a (604683), Kif3b, and Kap3 (601836) interacted with Nr2a (GRIN2A; 138253) and Apc (611731) as a complex in mouse brain. Kif3b was essential for postsynaptic localization of Nr2a and Nr2b (138252) in hippocampal neurons and was involved in transport of Nr2a, but not Nr2b, in dendrites. The authors found that a rare KIF3B nonsense mutation, arg354 to ter, identified in a patient with schizophrenia (see 181500) was functionally impaired, as it failed to restore spine morphology and surface Nr2a levels in mouse Kif3b +/- neurons.
Lawrence et al. (2004) presented a standardized kinesin nomenclature based on 14 family designations. Under this system, KIF3B belongs to the kinesin-2 family.
In a 5-year-old boy with retinitis pigmentosa (RP89; 618955), Cogne et al. (2020) identified heterozygosity for a de novo missense mutation in the KIF3B gene (E250Q; 603754.0001). Through GeneMatcher, the authors identified another missense mutation in KIF3B (L523P; 603754.0002) that segregated with disease in a 6-generation Ashkenazi Jewish family with autosomal dominant RP. Affected members of both families exhibited some features consistent with ciliopathy, such as polydactyly and renal or hepatic disease. Functional analysis demonstrated that the mutations cause increased primary cilia length and impaired trafficking of rhodopsin (RHO; 180380).
By gene targeting, Nonaka et al. (1998) disrupted the murine Kif3b gene. The null mutants did not survive beyond midgestation, exhibiting growth retardation, pericardial sac ballooning, and neural tube disorganization. Prominently, the left-right asymmetry was randomized in the heart loop and the direction of embryonic turning. Lefty2 (601877) expression was either bilateral or absent. Furthermore, the node lacked monocilia while the basal bodies were present. Immunocytochemistry revealed Kif3b localization in wildtype nodal cilia. Video microscopy showed that these cilia were motile and generated a leftward flow. These data suggested that KIF3B is essential for the left-right determination through intraciliary transportation of materials for ciliogenesis of motile primary cilia that could produce a gradient of putative morphogen along the left-right axis in the node.
Alsabban et al. (2020) found that Kif3b +/- mice exhibited schizophrenia-like phenotypes, both behaviorally and histologically. Hippocampal neurons of Kif3b +/- mice had altered spine morphology and synapse function, and at the cellular level, they displayed abnormal growth cone morphology.
Cogne et al. (2020) performed a genomewide association study in 98 Bengal cats with recessive progressive retinal atrophy. A missense mutation (A334T) in the Kif3b gene, predicted to impair the kinesin motor domain, was the sole variant that segregated with disease. The authors observed mislocalization of rhodopsin to photoreceptor inner segments in Kif3b -/- mutant kittens as early as 8 weeks of age, consistent with structural and functional photoreceptor degeneration.
In a 5-year-old boy (family A) with retinitis pigmentosa (RP89; 618955), Cogne et al. (2020) identified heterozygosity for a de novo c.748G-C transversion (c.748G-C, NM_004798.4) in exon 2 of the KIF3B gene, resulting in a glu250-to-gln (E250Q) substitution at a highly conserved residue within the kinesin motor domain. The mutation was not found in his unaffected parents or in the gnomAD database. Analysis of patient fibroblasts revealed that primary cilia length was increased significantly compared to those in age-matched control fibroblasts. In addition, cilia length in transfected hTERT-RPE1 cells showed a 9% increase with the E250Q mutant compared to wildtype KIF3B (p less than 0.01). Zebrafish embryos injected with the E250Q mutant showed marked lethality, and the highest nonlethal doses resulted in significant and dose-dependent reduction in eye area; coinjection of wildtype KIF3B mRNA restored eye size to normal. In addition, there was a modest but significant increase in apoptotic cells in retinal sections from larvae injected with the mutant compared to wildtype KIF3B. Evaluation of rhodopsin (RHO; 180380) localization in retinal sections at 5 days postfertilization (dpf) showed a significant increase of rhodopsin in the rod inner segment with the E250Q mutant compared to wildtype; coinjection with wildtype rescued the rhodopsin mislocalization defects. Analysis of ciliary markers in 5-dpf retinas showed significant elongation of photoreceptor connecting cilia with the mutant versus wildtype KIF3B. In addition to RP, the proband exhibited features of ciliopathy including postaxial polydactyly and hepatic disease.
In affected members of a 6-generation Ashkenazi Jewish family (family B) segregating autosomal dominant retinitis pigmentosa (RP89; 618955), Cogne et al. (2020) identified heterozygosity for a c.1568T-C transition (c.1568T-C, NM_004798.4) in exon 4 of the KIF3B gene, resulting in a leu523-to-pro (L523P) substitution at a highly conserved residue within the coiled-coil domain. The mutation was not present in an unaffected family member or in the gnomAD database. Functional analysis in transfected hTERT-RPE1 cells showed a 13% increase in cilia length with the L523P mutant compared to wildtype KIF3B (p less than 0.0001). Evaluation of rhodopsin (RHO; 180380) localization in retinal sections from zebrafish larvae at 5 days postfertilization (dpf) showed a significant increase of rhodopsin in the rod inner segment with the L523P mutant compared to wildtype; coinjection with wildtype rescued the rhodopsin mislocalization defects. Analysis of ciliary markers in 5-dpf retinas showed significant elongation of photoreceptor connecting cilia with the mutant versus wildtype KIF3B. Some affected family members also exhibited features of ciliopathy, including postaxial polydactyly or renal disease.
Alsabban, A. H., Morikawa, M., Tanaka, Y., Takei, Y., Hirokawa, N. Kinesin Kif3b mutation reduces NMDAR subunit NR2A trafficking and causes schizophrenia-like phenotypes in mice. EMBO J. 39: e101090, 2020. Note: Electronic Article. [PubMed: 31746486] [Full Text: https://doi.org/10.15252/embj.2018101090]
Cogne, B., Latypova, X., Senaratne, L. D. S., Martin, L., Koboldt, D. C., Kellaris, G., Fievet, L., Le Meur, G., Caldari, D., Debray, D., Nizon, M., Frengen, E., and 16 others. Mutations in the kinesin-2 motor KIF3B cause an autosomal-dominant ciliopathy. Am. J. Hum. Genet. 106: 893-904, 2020. [PubMed: 32386558] [Full Text: https://doi.org/10.1016/j.ajhg.2020.04.005]
Gross, M. B. Personal Communication. Baltimore, Md. 6/21/2012.
Lawrence, C. J., Dawe, R. K., Christie, K. R., Cleveland, D. W., Dawson, S. C., Endow, S. A., Goldstein, L. S. B., Goodson, H. V., Hirokawa, N., Howard, J., Malmberg, R. L., McIntosh, J. R., and 10 others. A standardized kinesin nomenclature. J. Cell Biol. 167: 19-22, 2004. [PubMed: 15479732] [Full Text: https://doi.org/10.1083/jcb.200408113]
Nagase, T., Ishikawa, K., Nakajima, D., Ohira, M., Seki, N., Miyajima, N., Tanaka, A., Kotani, H., Nomura, N., Ohara, O. Prediction of the coding sequences of unidentified human genes. VII. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro. DNA Res. 4: 141-150, 1997. [PubMed: 9205841] [Full Text: https://doi.org/10.1093/dnares/4.2.141]
Nonaka, S., Tanaka, Y., Okada, Y., Takeda, S., Harada, A., Kanai, Y., Kido, M., Hirokawa, N. Randomization of left-right asymmetry due to loss of nodal cilia generating leftward flow of extraembryonic fluid in mice lacking KIF3B motor protein. Cell 95: 829-837, 1998. Note: Erratum: Cell 99: 117 only, 1999. [PubMed: 9865700] [Full Text: https://doi.org/10.1016/s0092-8674(00)81705-5]
Yamazaki, H., Nakata, T., Okada, Y., Hirokawa, N. KIF3A/B: a heterodimeric kinesin superfamily protein that works as a microtubule plus end-directed motor for membrane organelle transport. J. Cell Biol. 130: 1387-1399, 1995. [PubMed: 7559760] [Full Text: https://doi.org/10.1083/jcb.130.6.1387]