Alternative titles; symbols
HGNC Approved Gene Symbol: SASS6
Cytogenetic location: 1p21.2 Genomic coordinates (GRCh38): 1:100,083,570-100,132,930 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p21.2 | Microcephaly 14, primary, autosomal recessive | 616402 | Autosomal recessive | 3 |
SAS6 is necessary for centrosome duplication and functions during procentriole formation; SAS6 functions to ensure that each centriole seeds the formation of a single procentriole per cell cycle (Strnad et al., 2007).
By searching databases for sequences containing a 'present in Sas6' (PISA) motif, followed by PCR, Leidel et al. (2005) cloned human SAS6. The deduced 657-amino acid protein contains an N-terminal PISA motif, followed by a coiled-coil region. Sas6 localized to centrioles at the onset of centrosome duplication in C. elegans. Fluorescence-tagged human SAS6 also localized to centrosomes in transfected human osteosarcoma cells.
Leidel et al. (2005) found that SAS6 overexpression in osteosarcoma cells resulted in an excess of centrioles, but it did not cause multinucleation or alter cell cycle progression. Inactivation of SAS6 with siRNA resulted in cells with monopolar spindles, followed by a failure of cytokinesis and cell death.
Through siRNA-mediated depletion and immunoelectron microscopy directed to individual centrosomal proteins, Kleylein-Sohn et al. (2007) found that PLK4 (605031), SAS6, CPAP (CENPJ; 609279), CEP135 (611423), TUBG1 (191135), and CP110 (609544) were required at different stages of procentriole formation and were associated with different centriolar structures. SAS6 associated only transiently with nascent procentrioles, whereas CEP135 and CPAP formed a core structure within the proximal lumen of both parental and nascent centrioles. Strnad et al. (2007) showed that SAS6 was necessary for procentriole formation in human cell lines, and that SAS6 localized asymmetrically next to the centriole at the onset of procentriole formation, prior to the recruitment of CETN2 (300006). SAS6 levels oscillated during the cell cycle; it was degraded in mitosis starting at anaphase, and it accumulated again at the end of the following G1 phase. The anaphase-promoting complex (APC; see ANAPC1, 608473) targeted SAS6 for degradation by the 26S proteasome, and a KEN box in the C terminus of SAS6 was required for its degradation. Strnad et al. (2007) also showed that increased SAS6 levels promoted the formation of multiple procentrioles forming next to a single centriole.
Khan et al. (2014) reported that the SASS6 gene has 17 exons.
Hartz (2005) mapped the SAS6 gene to chromosome 1p21.2 based on an alignment of the SAS6 sequence (GenBank AK025750) with the genomic sequence.
Crystal Structure
Van Breugel et al. (2011) determined the x-ray structure of the amino-terminal domain of SAS6 from zebrafish, and showed that recombinant SAS6 self-associates in vitro into assemblies that resemble cartwheel centers. Point mutations were consistent with the notion that centriole formation in vivo depends on the interactions that define the self-assemblies observed by them. Van Breugel et al. (2011) concluded that these interactions are probably essential to the structural organization of cartwheel centers.
In affected members of a consanguineous Pakistani family with autosomal recessive primary microcephaly-14 (MCPH14; 616402), Khan et al. (2014) identified a homozygous missense mutation in the SASS6 gene (I62T; 609321.0001). The mutation, which was found by a combination of linkage analysis and Sanger sequencing, segregated with the disorder in the family.
In a Chinese fetus with MCPH14, Zhang et al. (2019) identified compound heterozygous splice site mutations in the SASS6 gene (609321.0002; 609321.0003). The mutations were identified by whole-exome sequencing and confirmed by Sanger sequencing. Each parent was heterozygous for one of the mutations, both of which were classified as pathogenic according to ACMG guidelines. The fetus inherited an additional splice site mutation from the mother.
In 3 affected individuals from a 5-generation consanguineous Pakistani kindred with autosomal recessive primary microcephaly-14 (MCPH14; 616402), Khan et al. (2014) identified a homozygous c.185T-C transition (c.185T-C, NM_194292.1) in exon 3 of the SASS6 gene (chr1.100,588,787A-G, GRCh37), resulting in an ile62-to-thr (I62T) substitution at a conserved residue in the hydrophobic core of the protein. The mutation, which was found by a combination of homozygosity mapping and Sanger sequencing, segregated with the disorder in the family and was not found in 116 Pakistani controls or in the Exome Variant Server (ESP6500) database. Transfection of the mutant and wildtype proteins into human cells demonstrated that the I62T mutation impairs the centriole-forming function of SASS6, thus predicting defective cell division. A homozygous missense variant (S219L) in the CAPZA1 gene (601580) also segregated with the disorder, but was not thought to be pathogenic.
In a Chinese fetus with autosomal recessive primary microcephaly-14 (MCPH14; 616402), Zhang et al. (2019) identified compound heterozygous mutations in the SASS6 gene: a paternally inherited c.127-13A-G transition (c.127-13A-G, NM_194292) in intron 2, resulting in skipping of exon 3 and a truncated protein (Asp43PhefsTer49), and a maternally inherited c.1867+2T-A transversion in intron 16 (609321.0003), resulting in a truncated protein (Asn591LysfsTer54). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, were classified as pathogenic according to ACMG guidelines. The fetus inherited an additional mutation from the mother (c.1834C-G), which was classified as likely pathogenic according to ACMG guidelines. All 3 variants were absent from public databases and from an in-house database of 80,000 Chinese exomes.
For discussion of the c.1867+2T-A mutation (c.1867+2T-A, NM_194292) in the SASS6 gene, resulting in a truncated protein (Asn591LysfsTer54), that was found in compound heterozygous state in a fetus with autosomal recessive primary microcephaly-14 (MCPH14; 616402) by Zhang et al. (2019), see 609321.0002.
Hartz, P. A. Personal Communication. Baltimore, Md. 4/20/2005.
Khan, M. A., Rupp, V. M., Orpinell, M., Hussain, M. S., Altmuller, J., Steinmetz, M. O., Enzinger, C., Thiele, H., Hohne, W., Nurnberg, G., Baig, S. M., Ansar, M., Nurnberg, P., Vincent, J. B., Speicher, M. R., Gonczy, P., Windpassinger, C. A missense mutation in the PISA domain of HsSAS-6 causes autosomal recessive primary microcephaly in a large consanguineous Pakistani family. Hum. Molec. Genet. 23: 5940-5949, 2014. [PubMed: 24951542] [Full Text: https://doi.org/10.1093/hmg/ddu318]
Kleylein-Sohn, J., Westendorf, J., Le Clech, M., Habedanck, R., Stierhof, Y.-D., Nigg, E. A. Plk4-induced centriole biogenesis in human cells. Dev. Cell 13: 190-202, 2007. [PubMed: 17681131] [Full Text: https://doi.org/10.1016/j.devcel.2007.07.002]
Leidel, S., Delattre, M., Cerutti, L., Baumer, K., Gonczy, P. SAS-6 defines a protein family required for centrosome duplication in C. elegans and in human cells. Nature Cell Biol. 7: 115-125, 2005. [PubMed: 15665853] [Full Text: https://doi.org/10.1038/ncb1220]
Strnad, P., Leidel, S., Vinogradova, T., Euteneuer, U., Khodjakov, A., Gonczy, P. Regulated HsSAS-6 levels ensure formation of a single procentriole per centriole during the centrosome duplication cycle. Dev. Cell 13: 203-213, 2007. [PubMed: 17681132] [Full Text: https://doi.org/10.1016/j.devcel.2007.07.004]
van Breugel, M., Hirono, M., Andreeva, A., Yanagisawa, H., Yamaguchi, S., Nakazawa, Y., Morgner, N., Petrovich, M., Ebong, I.-O., Robinson, C. V., Johnson, C. M., Veprintsev, D., Zuber, B. Structures of SAS-6 suggest its organization in centrioles. Science 331: 1196-1199, 2011. [PubMed: 21273447] [Full Text: https://doi.org/10.1126/science.1199325]
Zhang, Y., Li, H., Pang, J., Peng, Y., Shu, L., Wang, H. Novel SASS6 compound heterozygous mutations in a Chinese family with primary autosomal recessive microcephaly. Clin. Chim. Acta 491: 15-18, 2019. [PubMed: 30639237] [Full Text: https://doi.org/10.1016/j.cca.2019.01.007]