Alternative titles; symbols
HGNC Approved Gene Symbol: KIZ
Cytogenetic location: 20p11.23 Genomic coordinates (GRCh38): 20:21,125,975-21,246,622 (from NCBI)
Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
---|---|---|---|---|
20p11.23 | Retinitis pigmentosa 69 | 615780 | Autosomal recessive | 3 |
KIZ is a centrosomal substrate of Polo-like kinase-1 (PLK1; 602098) that mediates mitotic chromosome stabilization (Oshimori et al., 2006).
Using a solid-phase phosphorylation screen to identify PLK1 substrates, followed by database searching, Oshimori et al. (2006) identified an uncharacterized gene that they named kizuna, or KIZ, after the Japanese word for bonds. The predicted protein contains 673 amino acids. Immunoblot analysis of HeLa cell lysates revealed a 100-kD protein, larger than the predicted mass of 75 kD, likely due to amino acid composition rather than posttranslational modifications. Immunofluorescence microscopy demonstrated a centrosomal localization for KIZ throughout the cell cycle. After centrosome duplication, KIZ usually remained with the centrosome containing the older centriole. During prophase, KIZ accumulated around both separating centrosomes.
El Shamieh et al. (2014) performed transcriptomic analysis in mice and observed mRNA levels of the mouse ortholog Plk1s1 in rod photoreceptors, as well as its decreased expression when photoreceptors degenerated in rd1 (180072) mice. RNA in situ hybridization demonstrated the presence of Plk1s1 mRNA in the outer nuclear layer of the mouse retina. In quantitative RT-PCR in human tissues, El Shamieh et al. (2014) observed that KIZ transcript was most abundant in the retina, followed by the retinal pigment epithelium, whole-blood cells, and fibroblasts. Immunofluorescent staining of serum-starved human fibroblasts showed KIZ localization to the basal body of monocilia.
El Shamieh et al. (2014) reported that the KIZ gene is 12 kb and comprises 13 exons.
Gross (2014) mapped the KIZ gene to chromosome 20p11.23 based on an alignment of the KIZ sequence (GenBank AF220187) with the genomic sequence (GRCh37).
Using RNA interference, Oshimori et al. (2006) found that knockdown of KIZ in HeLa cells resulted in severe abnormalities during mitosis, including more than 2 microtubule-containing gamma-tubulin (see 191135) foci, resulting in abnormal spindles. KIZ-depleted cells grew more slowly, had nuclear abnormalities, and underwent cell cycle arrest. Multipolar spindles formed in KIZ-depleted cells through fragmentation and dissociation of pericentriolar material from mature centrosomes. During mitosis of HeLa cells, KIZ protein levels increased slightly, and KIZ was phosphorylated on threonine residues, particularly thr379, by PLK1. Immunoprecipitation studies showed that KIZ interacted with the polo-box domain of PLK1. KIZ phosphorylation was indispensable for spindle-pole stabilization. KIZ also coimmunoprecipitated with several centrosomal components, including pericentrin (PCNT; 605925). Oshimori et al. (2006) concluded that KIZ protects mature centrosomes from collapse during spindle formation and proposed that KIZ functions as a bond that tethers the expanded pericentriolar material to the centriole. Alternatively, they suggested that KIZ may be required for proper assembly of pericentriolar material structural proteins, such as pericentrin, to create an architecture strong enough to withstand microtubule-mediated tensions applied to centrosomes.
In 3 unrelated patients with retinitis pigmentosa (RP69; 615780), El Shamieh et al. (2014) identified homozygosity or compound heterozygosity for truncating mutations in the KIZ gene (615757.0001-615757.0003). The authors stated that KIZ accounted for about 1% of disease in their cohort of 341 RP patients, but noted that this might represent a slight overestimation for autosomal recessive retinitis pigmentosa, since in the majority of their patients mutations in other retinal disease-associated genes had already been excluded.
In 2 unrelated men with retinitis pigmentosa (RP69; 615780), 1 of North African Sephardic Jewish ancestry and the other of Spanish ancestry, El Shamieh et al. (2014) identified homozygosity for a c.226C-T transition in exon 3 of the KIZ gene, resulting in an arg76-to-ter (R76X) substitution. This rare variant (rs202210819), which segregated with disease in the consanguineous North African family, was found in heterozygosity in 5 European Americans among 5,920 individuals in the NHLBI Exome Variant Server (MAF = 0.0004 in European Americans). Haplotype analysis in the 2 affected men revealed that they shared a common haplotype of 5 polymorphic microsatellites flanking KIZ, suggesting that R76X represents a founder mutation causing autosomal recessive RP in the southern European population.
In a 51-year-old man of mixed Italian and French descent who had retinitis pigmentosa (RP69; 615780), El Shamieh et al. (2014) identified compound heterozygosity for a c.52G-T transversion in exon 1 of the KIZ gene, resulting in a glu18-to-ter (E18X) substitution, and a 4-bp deletion (119_122delAACT; 615757.0003) in exon 2, predicted to result in a premature termination codon (Lys40IlefsTer14). The patient's unaffected parents were each heterozygous for 1 of the mutations.
For discussion of the 4-bp deletion (119_122delAACT) in exon 2 of the KIZ gene that was found in compound heterozygous state in a patient with retinitis pigmentosa (RP69; 615780) by El Shamieh et al. (2014), see 615757.0002.
El Shamieh, S., Neuille, M., Terray, A., Orhan, E., Condroyer, C., Demontant, V., Michiels, C., Antonio, A., Boyard, F., Lancelot, M.-E., Letexier, M., Saraiva, J.-P., Leveillard, T., Mohand-Said, S., Goureau, O., Sahel, J.-A., Zeitz, C., Audo, I. Whole-exome sequencing identifies KIZ as a ciliary gene associated with autosomal-recessive rod-cone dystrophy. Am. J. Hum. Genet. 94: 625-633, 2014. [PubMed: 24680887] [Full Text: https://doi.org/10.1016/j.ajhg.2014.03.005]
Gross, M. B. Personal Communication. Baltimore, Md. 4/24/2014.
Oshimori, N., Ohsugi, M., Yamamoto, T. The Plk1 target kizuna stabilizes mitotic centrosomes to ensure spindle bipolarity. Nature Cell Biol. 8: 1095-1101, 2006. [PubMed: 16980960] [Full Text: https://doi.org/10.1038/ncb1474]