HGNC Approved Gene Symbol: KLC2
SNOMEDCT: 725139005;
Cytogenetic location: 11q13.2 Genomic coordinates (GRCh38): 11:66,243,938-66,267,860 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11q13.2 | Spastic paraplegia, optic atrophy, and neuropathy | 609541 | Autosomal recessive | 3 |
Kinesin is a molecular motor that generates ATP-dependent movement of vesicles and organelles along microtubules. Kinesin consists of 2 light chains, such as KLC2, and 2 heavy chains (see KIF5B, 602809) in a 1:1 stoichiometric ratio (summary by Rahman et al., 1998). The KLC2 protein is involved in anterograde axoplasmatic transport of organelles and macromolecular cargoes (summary by Melo et al., 2015).
Rahman et al. (1998) cloned mouse Klc2. The deduced 599-amino acid protein has an N-terminal coiled-coil region of about 100 amino acids and 6 imperfect tetratricopeptide repeats of about 34 amino acids each. Northern and Western blot analyses detected Klc2 in all mouse tissues examined, with enrichment in central and peripheral neuronal tissues. Immunofluorescence analysis of cultured rat hippocampal precursor cells showed that Klc2 levels were not affected by differentiation. In situ hybridization of mouse brain showed that both Klc1 (600025) and Klc2 were enriched in olfactory bulb, hippocampus, dentate gyrus, and the granular layer of cerebellum. Within sciatic nerve, Klc2 was expressed in Schwann cells and localized within axons in a punctate pattern. Fractionation of whole mouse brain extracts revealed Klc1 and Klc2 in the cytosolic fraction and Klc2 in the microsomal fraction.
Gross (2016) mapped the KLC2 gene to chromosome 11q13.2 based on an alignment of the KLC2 sequence (GenBank BC034373) with the genomic sequence (GRCh38).
Using backcross analysis, Rahman et al. (1998) mapped the mouse Klc2 gene to the proximal end of chromosome 19 in a region that shares homology of synteny with human chromosome 11q12-q13.
Using anti-mouse Klc2 antibodies to immunoprecipitate proteins from mouse brain lysates, Rahman et al. (1998) showed that Klc2 associated with Nkhc (KIF5A; 602821) and Ukhc (KIF5B), but not with Klc1. In the presence of a nonhydrolyzable ATP analog, both Klc1 and Klc2 cosedimented with taxol-stabilized mouse brain microtubules.
By analyzing the virus capsid uncoating process during adenovirus infection in HeLa cells, Strunze et al. (2011) found that the incoming virus particle moved toward the nucleus via microtubules and docked to the nuclear pore complex (NPC) by interacting with Nup214 (114350). Adenovirus subsequently recruited kinesin-1 using viral capsid protein IX, which interacted with kinesin-1 light chain KLC1/KLC2. Kinesin-1 then bound to NUP358 (601181), which was attached to the NUP214/NUP88 (602552) complex, through its heavy chain KIF5C (604593) and disrupted the viral capsid and dislocated NUP214, NUP358, and NUP62 (605815) from the central NPC to the periphery. Disruption of the NPC increased permeability of the nuclear envelope and facilitated entry of viral DNA into the nucleus.
Crystal Structure
Pernigo et al. (2013) presented the crystal structure of the tetratricopeptide repeat domain of kinesin light chain-2 in complex with a cargo peptide harboring a tryptophan-acidic motif derived from SKIP (609613), a critical host determinant in Salmonella pathogenesis and a regulator of lysosomal positioning. Structural data together with biophysical, biochemical, and cellular assays allowed Pernigo et al. (2013) to propose a framework for intracellular transport based on the binding by kinesin-1 of W-acidic cargo motifs through a combination of electrostatic interactions and sequence-specific elements, providing direct molecular evidence of the mechanisms for kinesin-1:cargo recognition.
In 73 Brazilian patients and 2 sibs of Egyptian descent with spastic paraplegia, optic atrophy, and neuropathy (SPOAN; 609541), Melo et al. (2015) identified a homozygous 216-bp deletion in the noncoding upstream promoter region of the KLC2 gene (611729.0001). The deletion was not identified by whole-exome sequencing, but only by whole-genome sequencing. Patient fibroblasts and pluripotent stem cells induced into motor neurons showed increased expression of the KLC2 gene (increase of 48 to 74% compared to controls). Melo et al. (2015) noted that this was a novel molecular disease mechanism: a gain-of-function effect in a recessive disorder.
Melo et al. (2015) found that morpholino knockdown of the klc2 gene in zebrafish embryos resulted in a shortened and twisted tail and an inability to swim, in a dose-dependent manner. Overexpression of the klc2 gene resulted in a similar motor phenotype with increased lethality (over 70%).
Using an auditory brainstem response (ABR) test to screen knockout mice, Ingham et al. (2019) identified Klc2 as a gene underlying hearing loss in mice. Klc2-knockout mice showed a progressive increase in ABR thresholds with age, mostly affecting low frequencies, with a sensorineural (not conductive) pathology.
In 73 Brazilian patients and 2 sibs of Egyptian descent with spastic paraplegia, optic atrophy, and neuropathy (SPOAN; 609541), Melo et al. (2015) identified a homozygous 216-bp deletion (chr11.66,024,557_66,024,773del, GRCh37) in the noncoding upstream promoter region of the KLC2 gene. The deletion was not identified by whole-exome sequencing, but only by whole-genome sequencing. The mutation segregated with the disorder in the families and was not found in the 1000 Genomes Project database or in 474 Brazilian controls. Patient fibroblasts and pluripotent stem cells induced into motor neurons showed increased expression of the KLC2 gene (increase of 48 to 74% compared to controls). There were no differences in KLC2 expression in peripheral blood cells between patients, heterozygous mutation carriers, and controls, suggesting a tissue-specific effect. The 2 Egyptian sibs were previously reported by Novarino et al. (2014) as family 709: that report identified a homozygous c.2023T-C variant in the FLRT1 gene (604806) that was putatively responsible for the disorder, which they designated SPG68. However, Melo et al. (2015) concluded that the 216-bp KLC2 deletion was more likely to be the causative mutation in these patients.
Gross, M. B. Personal Communication. Baltimore, Md. 2/17/2016.
Ingham, N. J., Pearson, S. A., Vancollie, V. E., Rook, V., Lewis, M. A., Chen, J., Buniello, A., Martelletti, E., Preite, L., Lam, C. C., Weiss, F. D., Powis, Z., Suwannarat, P., Lelliott, C. J., Dawson, S. J., White, J. K., Steel, K. P. Mouse screen reveals multiple new genes underlying mouse and human hearing loss. PLoS Biol. 17: e3000194, 2019. Note: Electronic Article. [PubMed: 30973865] [Full Text: https://doi.org/10.1371/journal.pbio.3000194]
Melo, U. S., Macedo-Souza, L. I., Figueiredo, T., Muotri, A. R., Gleeson, J. G., Coux, G., Armas, P., Calcaterra, N. B., Kitajima, J. P., Amorim, S., Olavio, T. R., Griesi-Oliveira, K., Coatti, G. C., Rocha, C. R. R., Martins-Pinheiro, M., Menck, C. F. M., Zaki, M. S., Kok, F., Zatz, M., Santos, S. Overexpression of KLC2 due to a homozygous deletion in the non-coding region causes SPOAN syndrome. Hum. Molec. Genet. 24: 6877-6885, 2015. [PubMed: 26385635] [Full Text: https://doi.org/10.1093/hmg/ddv388]
Novarino, G., Fenstermaker, A. G., Zaki, M. S., Hofree, M., Silhavy, J., Heiberg, A. D., Abdellateef, M., Rosti, B., Scott, E., Mansour, L., Masri, A., Kayserili, H., and 41 others. Exome sequencing links corticospinal motor neuron disease to common neurodegenerative disorders. Science 343: 506-511, 2014. [PubMed: 24482476] [Full Text: https://doi.org/10.1126/science.1247363]
Pernigo, S., Lamprecht, A., Steiner, R. A., Dodding, M. P. Structural basis for kinesin-1:cargo recognition. Science 340: 356-359, 2013. [PubMed: 23519214] [Full Text: https://doi.org/10.1126/science.1234264]
Rahman, A., Friedman, D. S., Goldstein, L. S. B. Two kinesin light chain genes in mice: identification and characterization of the encoded proteins. J. Biol. Chem. 273: 15395-15403, 1998. Note: Erratum: J. Biol. Chem. 273: 24280 only, 1998. [PubMed: 9624122] [Full Text: https://doi.org/10.1074/jbc.273.25.15395]
Strunze, S., Engelke, M. F., Wang, I-H., Puntener, D., Boucke, K., Schleich, S., Way, M., Schoenenberger, P., Burckhardt, C. J., Greber, U. F. Kinesin-1-mediated capsid disassembly and disruption of the nuclear pore complex promote virus infection. Cell Host Microbe 10: 210-223, 2011. [PubMed: 21925109] [Full Text: https://doi.org/10.1016/j.chom.2011.08.010]