Alternative titles; symbols
HGNC Approved Gene Symbol: USH1G
Cytogenetic location: 17q25.1 Genomic coordinates (GRCh38) : 17:74,916,083-74,923,255 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17q25.1 | Usher syndrome, type 1G | 606943 | Autosomal recessive | 3 |
SANS plays a role in regulating endocytosis-dependent ciliogenesis (Bauss et al., 2014).
By positional cloning, Kikkawa et al. (2003) identified a novel gene within the 72-kb region on mouse chromosome 11 containing the Jackson shaker (js) locus. Kikkawa et al. (2003) named the gene Sans because it was found to encode a scaffold protein containing ankyrin repeats and a SAM (sterile alpha motif) domain. Kikkawa et al. (2003) determined that the mouse protein is expressed in the cochlea (including inner and outer hair cells), cerebellum, eye, and testis.
Weil et al. (2003) cloned the human homolog of the mouse Sans gene in silico by database mining. The deduced 460-amino acid protein contains 3 ankyrin-like domains near the N terminus, a central region, and a SAM domain and a PDZ-binding motif at the C terminus. The human protein shares 96% sequence identity with the mouse protein.
By immunohistochemical analysis of mouse retina, Bauss et al. (2014) detected Sans at the base of the connecting cilium in photoreceptor cells, where it localized to a periciliary membrane complex facing the ciliary pocket.
Weil et al. (2003) determined that the human SANS gene spans over 7.2 kb and contains 3 exons, 2 of which are coding.
Kikkawa et al. (2003) identified the Sans gene within the critical region of the Jackson shaker mouse mutation on chromosome 10. This region shows syntenic homology with a region of human chromosome 17 to which the Usher syndrome type IG (USH1G; 606943) locus had been mapped (17q24-q25). By sequence analysis, Weil et al. (2003) identified the SANS gene on chromosome 17 between markers D17S1807 and D17S1839.
Weil et al. (2003) found by cotransfection experiments that SANS interacts with harmonin (USH1C; 605242), which is mutant in Usher syndrome type IC (276904). The authors proposed that SANS is an integral part of the protein complex linking cadherin (CDH23; 605516) stereocilia laterally to the stereocilia microfilaments. CDH23 is mutant in Usher syndrome type ID (USH1D; 601067)
By using cotransfection and immunolocalization techniques, Adato et al. (2005) documented the interaction between SANS and harmonin, and also determined that SANS binds to myosin VIIa (MYO7A; 276903). The authors noted that SANS formed homomeric structures. SANS was localized to the apical region of cochlear and vestibular hair cell bodies underneath the cuticular plate. In contrast to the other 4 known USH1 proteins, no SANS labeling was detected within the stereocilia. Adato et al. (2005) proposed that via its binding to myosin VIIa and/or harmonin, SANS controls the hair bundle cohesion and proper development by regulating the traffic of USH1 proteins en route to the stereocilia.
Using yeast 2-hybrid analysis, Maerker et al. (2008) found that the C terminus of human SANS interacted with the N-terminal region of whirlin (WHRN; 607928) in a bovine retina cDNA library. In mouse retina, both proteins colocalized at synapses in the outer plexiform layer and in the outer limiting membrane, the inner segment, and the ciliary region of photoreceptor cells. Within the ciliary region, high resolution analysis revealed that Sans and whirlin colocalized in the connecting cilium and basal body complex. Maerker et al. (2008) showed that Sans provided a link to the microtubule transport machinery, whereas whirlin appeared to anchor 2 retinal transmembrane proteins, Ush2a (608400) isoform b and Vlgr1b (GPR98; 602851), to specific membrane domains. Maerker et al. (2008) concluded that this network of proteins may cooperate to regulate cargo transfer from inner segment transport carriers to the ciliary transport system of photoreceptors.
Bauss et al. (2014) found that endocytosis was required for ciliogenesis in mouse photoreceptors and ciliated kidney cells and that Sans negatively regulated this process. Yeast 2-hybrid analysis showed that Sans interacted with Magi2 (606382), a scaffold protein with a role in endocytosis and synapse formation. Mutation of bovine and mouse constructs revealed that a conserved SDLDL motif within the C-terminal SAM domain of Sans interacted with the PDZ domain-6 at the C terminus of Magi2. CK2 (see 115440)-dependent serine phosphorylation within the SDLDL motif of Sans increased Sans-Magi2 interaction and inhibited Magi2- and clathrin-dependent endocytosis and ciliogenesis. Knockdown of Sans or Magi2 inhibited both endocytosis and ciliogenesis in mouse IMCD3 cells in a manner similar to pharmacologic inhibition of clathrin-dependent endocytosis. In addition, knockdown of Sans resulted in a small percentage of cells with abnormally elongated cilia. Bauss et al. (2014) observed that several SANS mutations identified in patients with Usher syndrome type IG truncate the protein and abrogate binding of SANS to MAGI2. The authors concluded that MAGI2-mediated endocytosis is required for ciliogenesis and that phosphorylated SANS negatively regulates MAGI2-mediated endocytosis.
Crystal Structure
Wu et al. (2011) reported the crystal structure of the MyTH4-FERM domains of MYO7A in complex with the central domain (CEN) of SANS at 2.8-angstrom resolution. The MyTH4 and FERM domains form an integral structural and functional supramodule binding to 2 highly conserved segments (CEN1 and 2) of SANS. Wu et al. (2011) concluded that the MyTH4-FERM/CEN complex structure provides mechanistic explanations for known deafness-causing mutations in MYO7A MyTH4-FERM.
In affected members of a large Tunisian family segregating Usher syndrome type IG (USH1G; 606943), Weil et al. (2003) identified a homozygous mutation in the SANS gene (607696.0004). They identified different homozygous or compound heterozygous mutations in the SANS gene in affected members of German and Jordanian families (see 607696.0001-607696.0003).
The Jackson shaker mouse carries a recessive mutation causing the phenotype of deafness, abnormal behavior (circling and/or head tossing) and degeneration of inner ear neuroepithelia (Kitamura et al., 1992). Kikkawa et al. (2003) noted that 2 alleles had been identified, the original js and jsseal. They determined that the Sans gene contains insertion mutations in both js and jsseal mutant alleles. Both mutations are predicted to inactivate the Sans protein by creating frameshift mutations, resulting in a truncated protein lacking the C-terminal SAM domain. Cochlear hair cells in the js mutants showed disorganized stereocilia bundles. Sans was shown by in situ hybridization to be highly expressed in both inner and outer hair cells of cochlea. Kikkawa et al. (2003) suggested that the existence of major motifs, ankyrin repeats and a SAM domain, supported an important role for Sans in the development and maintenance of the stereocilia bundles, possibly via protein-protein interactions.
In 2 German brothers with Usher syndrome type IG (USH1G; 606943), Weil et al. (2003) identified compound heterozygosity for mutations in the SANS gene. One mutation was a 142C-T transition in exon 1, predicting a substitution of proline for a relatively conserved leucine at position 48 (L48P) in the first ankyrin domain. The other mutation was a dinucleotide deletion in exon 2, 186delCA (607696.0002), predicted to produce a truncated 132-amino acid protein containing 70 missense C-terminal residues.
For discussion of the 2-bp deletion in the SANS gene (186delCA) that was found in compound heterozygous state in 2 brothers with Usher syndrome type IG (USH1G; 606943) by Weil et al. (2003), see 607696.0001.
In affected members of a consanguineous Jordanian family segregating Usher syndrome type IG (USH1G; 606943), Weil et al. (2003) identified homozygosity for a 20-bp deletion (nucleotides 829-848) in exon 2 of the SANS gene, predicting a truncated 326-amino acid protein containing 70 missense C-terminal residues and lacking the SAM domain.
In affected members of a consanguineous Tunisian family segregating Usher syndrome type IG (USH1G; 606943), Weil et al. (2003) identified homozygosity for a 393G insertion in exon 2 of the SANS gene, predicting a truncated 133-amino acid protein lacking the central region and the C-terminal SAM domain.
In a mutation screen of patients with Usher syndrome type I from the U.S. and the U.K., Ouyang et al. (2005) found homozygosity for a 113G-A transition in the USH1G gene, resulting in a trp38-to-ter (W38X) substitution in the first ankyrin domain of the SANS protein (see USH1G; 606943). The mutation would result in a truncated protein lacking approximately 90% of the predicted coding sequence. Ouyang et al. (2005) found the mutation in 2 (3.4%) of 59 probands from the U.S.
In 4 affected members of a consanguineous Pakistani family with Usher syndrome type IG (USH1G; 606943), Bashir et al. (2010) identified a homozygous 15-bp deletion (163_164+13del15) involving nucleotides in the first exon and intron of the USH1G gene. The mutation was not found in 200 control chromosomes. Investigation of the effect of the mutation was hampered because RNA from patient blood did not show sufficient expression of SANS. In silico analysis predicted that retention of the first intron in the RNA resulting from the mutation would introduce a frameshift and premature termination, which could result in nonsense-mediated mRNA decay. However, if the mRNA is processed, the frameshift would result in a truncated nonfunctional protein of 58 amino acids. The patients had an atypical form of Usher syndrome, with moderate to severe hearing loss, normal vestibular function, and lack of eyesight problems. However, funduscopy showed mild symptoms of retinitis pigmentosa and pale optic discs in 3 of the older affected patients at ages 13, 15, and 22 years, respectively. The findings indicated that even a truncating mutation in the USH1G gene can result in a relatively mild phenotype.
Adato, A., Michel, V., Kikkawa, Y., Reiners, J., Alagramam, K. N., Weil, D., Yonekawa, H., Wolfrum, U., El-Amraoui, A., Petit, C. Interactions in the network of Usher syndrome type 1 proteins. Hum. Molec. Genet. 14: 347-356, 2005. [PubMed: 15590703] [Full Text: https://doi.org/10.1093/hmg/ddi031]
Bashir, R., Fatima, A., Naz, S. A frameshift mutation in SANS results in atypical Usher syndrome. (Letter) Clin. Genet. 78: 601-603, 2010. [PubMed: 21044053] [Full Text: https://doi.org/10.1111/j.1399-0004.2010.01500.x]
Bauss, K., Knapp, B., Jores, P., Roepman, R., Kremer, H., v. Wijk, E., Marker, T., Wolfrum, U. Phosphorylation of the Usher syndrome 1G protein SANS controls Magi2-mediated endocytosis. Hum. Molec. Genet. 23: 3923-3942, 2014. [PubMed: 24608321] [Full Text: https://doi.org/10.1093/hmg/ddu104]
Kikkawa, Y., Shitara, H., Wakana, S., Kohara, Y., Takada, T., Okamoto, M., Taya, C., Kamiya, K., Yoshikawa, Y., Tokano, H., Kitamura, K., Shimizu, K., Wakabayashi, Y., Shiroishi, T., Kominami, R., Yonekawa, H. Mutations in a new scaffold protein Sans cause deafness in Jackson shaker mice. Hum. Molec. Genet. 12: 453-461, 2003. [PubMed: 12588793] [Full Text: https://doi.org/10.1093/hmg/ddg042]
Kitamura, K., Kakoi, H., Yoshikawa, Y., Ochikubo, F. Ultrastructural findings in the inner ear of Jackson shaker mice. Acta Otolaryng. 112: 622-627, 1992. [PubMed: 1442008] [Full Text: https://doi.org/10.3109/00016489209137451]
Maerker, T., van Wijk, E., Overlack, N., Kersten, F. F. J., McGee, J., Goldmann, T., Sehn, E., Roepman, R., Walsh, E. J., Kremer, H., Wolfrum, U. A novel Usher protein network at the periciliary reloading point between molecular transport machineries in vertebrate photoreceptor cells. Hum. Molec. Genet. 17: 71-86, 2008. [PubMed: 17906286] [Full Text: https://doi.org/10.1093/hmg/ddm285]
Ouyang, X. M., Yan, D., Du, L. L., Hejtmancik, J. F., Jacobson, S. G., Nance, W. E., Li, A. R., Angeli, S., Kaiser, M., Newton, V., Brown, S. D. M., Balkany, T., Liu, X. Z. Characterization of Usher syndrome type I gene mutations in an Usher syndrome patient population. Hum. Genet. 116: 292-299, 2005. [PubMed: 15660226] [Full Text: https://doi.org/10.1007/s00439-004-1227-2]
Weil, D., El-Amraoui, A., Masmoudi, S., Mustapha, M., Kikkawa, Y., Laine, S., Delmaghani, S., Adato, A., Nadifi, S., Ben Zina, Z., Hamel, C., Gal, A., Ayadi, H., Yonekawa, H., Petit, C. Usher syndrome type IG (USH1G) is caused by mutations in the gene encoding SANS, a protein that associates with the USH1C protein, harmonin. Hum. Molec. Genet. 12: 463-471, 2003. [PubMed: 12588794] [Full Text: https://doi.org/10.1093/hmg/ddg051]
Wu, L., Pan, L., Wei, Z., Zhang, M. Structure of MyTH4-FERM domains in myosin VIIa tail bound to cargo. Science 331: 757-760, 2011. [PubMed: 21311020] [Full Text: https://doi.org/10.1126/science.1198848]