Alternative titles; symbols
HGNC Approved Gene Symbol: SPAG17
Cytogenetic location: 1p12 Genomic coordinates (GRCh38) : 1:117,953,590-118,185,228 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p12 | ?Spermatogenic failure 55 | 619380 | Autosomal recessive | 3 |
Cilia play key roles in determining left-right asymmetry, clearing mucus, particles, and fluid from airways, and facilitating the flow of cerebrospinal fluid. The axoneme of motile cilia has a 9+2 arrangement of 9 outer doublet microtubules surrounding a central pair of microtubules, designated C1 and C2. SPAG17 is a component of the central pair apparatus of ciliary axonemes (Teves et al., 2013).
Using Chlamydomonas reinhardtii Pf6 to search databases, followed by PCR of testis total RNA, Zhang et al. (2005) cloned mouse and human SPAG17, which they designated PF6. The full-length human cDNA (GenBank AY555274) encodes a deduced 2,223-amino acid protein with an N-terminal proline-rich domain. The full-length mouse cDNA (GenBank AY792594) encodes a deduced 2,175-amino acid protein. Zhang et al. (2005) also cloned a splice variant of mouse Pf6 (GenBank AY555275) that encodes an 875-amino acid protein. Full-length human, mouse, and Chlamydomonas PF6 share 2 regions of significant similarity, one immediately after the proline-rich N-terminal region of human and Chlamydomonas PF6, and the other at the C terminus. Northern blot analysis detected highest expression of a 7.5-kb PF6 transcript in human testis, with much lower expression in brain, oviduct, lung, and uterus. A similar pattern of expression was detected for mouse Pf6. In mouse testis, Pf6 expression peaked at 20 days of postnatal life, when round spermatids appear and the flagellum is assembled. Western blot analysis of mouse testis detected proteins with apparent molecular masses of 250 and 97 kD, consistent with the predicted molecular masses of full-length Pf6 and the 875-amino acid isoform, respectively. Western blot analysis with antibodies directed to the N and C termini of the 97-kD mouse Pf6 isoform suggested processing of this isoform during spermatogenesis into N- and C-terminal fragments with apparent molecular masses of 72 and 28 kD, respectively. Immunohistochemical analysis of mouse sperm detected Pf6 along the length of the tail of epididymal sperm. Immunoelectron microscopy localized Pf6 asymmetrically at the central pair of microtubules in the sperm flagellar axoneme, suggesting that it may associate with a specific axonemal microtubule.
By coimmunostaining, Kazarian et al. (2018) analyzed Spag17 expression in mixed germ cells from 6-week-old mice and observed that Spag17 was present in the cytoplasm of germ cells and colocalized with the manchette microtubule structures in elongating spermatids. In sperm, Spag17 decorated the tail and acrosome. Spag17 colocalization with the acrosome and the Golgi apparatus was confirmed using a PSA lectin marker.
Baida et al. (2008) stated that the SPAG17 gene maps to chromosome 1p12.
By coimmunoprecipitation analysis of transfected CHO cells, Zhang et al. (2005) found that the isolated C-terminal domain of the 97-kD mouse Pf6 isoform interacted with mouse Spag6 (605730). The 97-kD Pf6 isoform colocalized with Spag6 and decorated microtubules in cotransfected cells. The 28-kD C-terminal fragment of Pf6 was missing from epididymal sperm in Spag6 -/- mice, which showed loss of the central pair of microtubules in the axoneme. In contrast, localization of the axonemal 72-kD N-terminal fragment of Pf6 was unaffected in Spag6 -/- epididymal sperm.
In a consanguineous Chinese family in which infertile twin brothers had severely reduced sperm motility (SPGF55; 619380), Xu et al. (2018) identified homozygosity for a missense mutation in the SPAG17 gene (R1448Q; 616554.0001) that segregated fully with disease.
Teves et al. (2013) found that Spag17 -/- mice were born at the expected mendelian ratio, but that they died within 12 hours of birth with severe defects in motile cilia. The phenotype of Spag17 -/- pups included immotile nasal and tracheal cilia, reduced clearance of nasal mucus, profound respiratory distress associated with lung fluid accumulation and disruption of alveolar epithelium, cerebral ventricular expansion consistent with emerging hydrocephalus, and failure to suckle. Ultrastructural analysis revealed loss of 1 central pair microtubule in approximately 25% of Spag17 -/- tracheal cilia axonemes, absence of a C1 microtubule projection, and other less frequent central pair structural abnormalities. Central pair proteins that interact with Spag17, such as Spag6 and Spag16 (612173), were increased in tracheal tissue from Spag17 -/- mice. Teves et al. (2013) concluded that SPAG17 plays a critical role in the function and structure of motile cilia.
Teves et al. (2015) reported that hindlimbs of Spag17 -/- newborn mouse pups were shorter than wildtype. The phenotype appeared to be due to altered patterning of femur and tibia, with premature ossification in femur and delayed cartilage and bone formation in tibia. Other skeletal malformations included fused sternebrae and reduced mineralization in skull and medial and metacarpal phalanges. Primary cilia from chondrocytes, osteoblasts, and embryonic fibroblasts (MEFs) isolated from Spag17 -/- mice were shorter, and fewer cells had primary cilia compared with wildtype. Knockdown of Spag17 in wildtype MEFs via small interfering RNA reproduced the short primary cilia phenotype.
Using a conditional knockout mouse model, Kazarian et al. (2018) generated Spag17-null mice and observed male infertility due to a severe defect in spermatogenesis. Histologic evaluation of testis sections from mutant mice revealed seminiferous tubules with spermatogenesis arrested at the spermatid stage and cell debris in the cauda epididymis. The few sperm collected from the cauda epididymis were immotile and displayed abnormal tail and head morphology. Immunofluorescence analysis of Spag17 knockout germ cells showed spermatids with abnormally long manchette structures and morphologic defects in the head. Electron microscopy showed altered manchette microtubules, reduced chromatin condensation, irregular nuclear shape, and detached acrosomes. Additionally, the transport of proteins along the manchette microtubules was disrupted in the knockout elongating spermatids.
In infertile twin brothers with severely reduced sperm motility (SPGF55; 619380), Xu et al. (2018) identified homozygosity for a c.4343G-A transition (c.4343G-A, NM_206996) in exon 30 of the SPAG17 gene, resulting in an arg1448-to-gln (R1448Q) substitution at a highly conserved residue. Their unaffected consanguineous parents and a fertile brother were heterozygous for the mutation, which was present at low minor allele frequency (0.0016) in the East Asian population of the ExAC database. Immunofluorescence analysis of patient sperm showed low SPAG17 expression in the flagella compared to wildtype; the low expression level was confirmed by Western blot.
Baida, A., Akdi, M., Gonzalez-Flores, E., Galofre, P., Marcos, R., Velazquez, A. Strong association of chromosome 1p12 loci with thyroid cancer susceptibility. Cancer Epidemiol. Biomarkers Prev. 17: 1499-1504, 2008. [PubMed: 18559567] [Full Text: https://doi.org/10.1158/1055-9965.EPI-07-0235]
Kazarian, E., Son, H., Sapao, P., Li, W., Zhang, Z., Strauss, J. F., III, Teves, M. E. SPAG17 is required for male germ cell differentiation and fertility. Int. J. Molec. Sci. 19: 1252, 2018. [PubMed: 29690537] [Full Text: https://doi.org/10.3390/ijms19041252]
Teves, M. E., Sundaresan, G., Cohen, D. J., Hyzy, S. L., Kajan, I., Maczis, M., Zhang, Z., Costanzo, R. M., Zweit, J., Schwartz, Z., Boyan, B. D., Strauss, J. F., III. Spag17 deficiency results in skeletal malformations and bone abnormalities. PLoS One 10: e0125936, 2015. [PubMed: 26017218] [Full Text: https://doi.org/10.1371/journal.pone.0125936]
Teves, M. E., Zhang, Z., Costanzo, R. M., Henderson, S. C., Corwin, F. D., Zweit, J., Sundaresan, G., Subler, M., Salloum, F. N., Rubin, B. K., Strauss, J. F., III. Sperm-associated antigen-17 gene is essential for motile cilia function and neonatal survival. Am. J. Resp. Cell Molec. Biol. 48: 765-772, 2013. [PubMed: 23418344] [Full Text: https://doi.org/10.1165/rcmb.2012-0362OC]
Xu, X., Sha, Y.-W., Mei, L.-B., Ji, Z.-Y., Qiu, P., Ji, H., Li, P., Wang, T., Li, L. A familial study of twins with severe asthenozoospermia identified a homozygous SPAG17 mutation by whole-exome sequencing. Clin. Genet. 93: 345-349, 2018. [PubMed: 28548327] [Full Text: https://doi.org/10.1111/cge.13059]
Zhang, Z., Jones, B. H., Tang, W., Moss, S. B., Wei, Z., Ho, C., Pollack, M., Horowitz, E., Bennett, J., Baker, M. E., Strauss, J. F., III. Dissecting the axoneme interactome: the mammalian orthologue of Chlamydomonas PF6 interacts with sperm-associated antigen 6, the mammalian orthologue of Chlamydomonas PF16. Molec. Cell. Proteomics 4: 914-923, 2005. [PubMed: 15827353] [Full Text: https://doi.org/10.1074/mcp.M400177-MCP200]