Alternative titles; symbols
HGNC Approved Gene Symbol: STK36
Cytogenetic location: 2q35 Genomic coordinates (GRCh38) : 2:218,672,086-218,702,717 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q35 | ?Ciliary dyskinesia, primary, 46 | 619436 | Autosomal recessive | 3 |
The STK36 gene encodes a serine/threonine protein kinase with a conserved role in ciliary and flagellar motility. STK36 plays a role in the assembly of components of the central pair apparatus of motile cilia and also contributes to the functional integrity of the central pair-radial spoke interaction (Edelbusch et al., 2017).
By sequencing clones obtained from a size-fractionated adult brain cDNA library, Nagase et al. (1999) cloned STK36, which they designated KIAA1278. The deduced 1,311-amino acid protein shares about 55% identity over 795 amino acids with the Drosophila 'fused' (Fu) protein. RT-PCR ELISA detected expression of STK36 at low to moderate levels in most tissues tested, but not in adult skeletal muscle and fetal liver.
Using Drosophila Fu as query, Murone et al. (2000) identified an EST containing STK36, and they used this sequence to screen fetal lung and adult testis cDNA libraries to obtain the full-length cDNA. The deduced 1,315-amino acid protein shares 55% homology with Drosophila Fu in the N-terminal kinase domain, but only limited homology over the remaining 1,052 amino acids. Northern blot analysis detected a 5.0-kb transcript expressed at low levels in most fetal tissues and in adult testis and ovary. Highest expression was in testis.
Edelbusch et al. (2017) stated that the STK36 gene contains 27 exons.
By radiation hybrid analysis, Nagase et al. (1999) mapped the STK36 gene to chromosome 2. Murone et al. (2000) stated that they mapped the STK36 gene to chromosome 2q35, close to the PAX3 gene (606597).
Noting that the Drosophila Fu protein modulates the activity of transcription factors, Murone et al. (2000) characterized the effects of STK36 on the transcriptional activities of GLI1 (165220), GLI2 (165230), and GLI3 (165240) in cotransfected mouse mesenchymal stem cells. STK36 did not affect the activity of GLI1 and GLI3, but strongly synergized with GLI2. Mutation analysis indicated that STK36 lacking the kinase domain was equally active. Murone et al. (2000) showed that SUFU (607035) repressed the transcription-enhancing activity of STK36. STK36 coimmunoprecipitated with SUFU, GLI1, GLI2, and GLI3 in cotransfected 293 cells. In the presence of SUFU, about 3% of cells exhibited nuclear staining of GLI1 or GLI2. When STK36 was introduced, however, about 20% of cells possessed nuclear GLI1 or GLI2 staining. Murone et al. (2000) concluded that STK36 controls the activity of GLI1 and GLI2 by opposing the effect of SUFU.
Wilson et al. (2009) demonstrated that mouse Fu is essential for construction of the central pair apparatus of motile, 9+2 cilia, and offers a new model of human primary ciliary dyskinesia (see 244400). They found that mouse Fu physically interacts with Kif27 (611253), a mammalian Cos2 ortholog, and linked Fu to known structural components of the central pair apparatus, providing evidence for the first regulatory component involved in central pair construction. Wilson et al. (2009) also demonstrated that zebrafish Fu is required both for hedgehog (see 600725) signaling and cilia biogenesis in Kupffer vesicle. Mouse Fu rescued both hedgehog-dependent and -independent defects in zebrafish. Wilson et al. (2009) concluded that their results delineated a new pathway for central pair apparatus assembly, identified common regulators of hedgehog signaling and motile ciliogenesis, and provided insights into the evolution of the hedgehog cascade.
In a 40-year-old Arab Israeli man with primary ciliary dyskinesia (CILD46; 619436), Edelbusch et al. (2017) identified homozygosity for a 1-bp deletion in the STK36 gene (607652.0001). Functional analysis revealed mislocalization of mutant STK36 on respiratory cilia, causing defects in the central pair/radial spokes interaction that result in disorientation of the central pair.
Fu has an essential role in hedgehog (SHH; 600725) signaling in Drosophila, and its deletion is embryonic lethal. In contrast, Chen et al. (2005) found that Fu-deficient mice were born at the expected mendelian ratio. Mutant mice could not be distinguished from wildtype littermates and appeared to develop normally. However, most Fu-deficient mice died before 3 weeks of age, apparently of starvation. Histologic examination showed no significant morphologic changes, and expression studies revealed no changes in hedgehog signaling. Chen et al. (2005) concluded that Fu does not have an essential role in hedgehog signaling in vertebrates.
In 40-year-old Arab Israeli man from a consanguineous family who had primary ciliary dyskinesia with situs solitus (CILD46; 619436), Edelbusch et al. (2017) identified homozygosity for a 1-bp deletion (c.1399delG) in the STK36 gene, causing a frameshift predicted to result in a premature termination codon (Glu467ArgfsTer13). The deletion was not found in the 1000 Genomes Project database, and was present at an allele frequency of less than 1 in 10,000 in the ExAC database. Transmission electron microscopy (TEM) of ciliary cross-sections from patient respiratory epithelial cells showed abnormal axonemal composition, with a 9+0 or 8+0 architecture, in less than 5% of cilia. Additional TEM analysis revealed that ciliary basal feet were not equally aligned, and were found at disorganized angles or in opposing orientation, resulting in an increased degree of disorientation of central pairs (CPs) compared to control cilia. STK36 was undetectable by immunofluorescence microscopy of patient respiratory epithelial cells, whereas it localized along the entire axonemal length in control respiratory cells. Because the phenotype in STK36-mutant cilia was reminiscent of a radial spoke (RS) defect, the authors analyzed whether localization of STK36 was altered in respiratory cilia of patients with loss-of-function (LOF) mutations in the RSPH1 (609314), RSPH4A (612647), or RSPH9 (612648) genes, and found that STK36 was undetectable in the ciliary axonemes of individuals carrying LOF mutations in each of the 3 RSPH genes. The authors concluded that STK36 is not necessary for the assembly of the RS head, but an intact head is essential for axonemal recruitment of STK36, and that STK36 plays an important role in the connection of RS heads to the CP complex.
Chen, M.-H., Gao, N., Kawakami, T., Chuang, P.-T. Mice deficient in the Fused homolog do not exhibit phenotypes indicative of perturbed hedgehog signaling during embryonic development. Molec. Cell. Biol. 25: 7042-7053, 2005. [PubMed: 16055716] [Full Text: https://doi.org/10.1128/MCB.25.16.7042-7053.2005]
Edelbusch, C., Cindric, S., Dougherty, G. W., Loges, N. T., Olbrich, H., Rivlin, J., Wallmeier, J., Pennekamp, P., Amirav, I., Omran, H. Mutation of serine/threonine protein kinase 36 (STK36) causes primary ciliary dyskinesia with a central pair defect. Hum. Mutat. 38: 964-969, 2017. [PubMed: 28543983] [Full Text: https://doi.org/10.1002/humu.23261]
Murone, M., Luoh, S.-M., Stone, D., Li, W., Gurney, A., Armanini, M., Grey, C., Rosenthal, A., de Sauvage, F. J. Gli regulation by the opposing activities of Fused and Suppressor of Fused. Nature Cell Biol. 2: 310-3112, 2000. [PubMed: 10806483] [Full Text: https://doi.org/10.1038/35010610]
Nagase, T., Ishikawa, K., Kikuno, R., Hirosawa, M., Nomura, N., Ohara, O. Prediction of the coding sequences of unidentified human genes. XV. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 6: 337-345, 1999. [PubMed: 10574462] [Full Text: https://doi.org/10.1093/dnares/6.5.337]
Wilson, C. W., Nguyen, C. T., Chen, M.-H., Yang, J.-H., Gacayan, R., Huang, J., Chen, J.-N., Chuang, P.-T. Fused has evolved divergent roles in vertebrate hedgehog signalling and motile ciliogenesis. Nature 459: 98-102, 2009. [PubMed: 19305393] [Full Text: https://doi.org/10.1038/nature07883]