Usher syndrome type I G (USH1G) is caused by mutations in the gene encoding SANS, a protein that associates with the USH1C protein, harmonin

Abstract

Usher syndrome type I (USH1) is the most frequent cause of hereditary deaf-blindness in humans. Seven genetic loci (USH1A-G) have been implicated in this disease to date, and four of the corresponding genes have been identified: USH1B, C, D and F. We carried out fine mapping of USH1G (chromosome 17q24-25), restricting the location of this gene to an interval of 2.6 Mb and then screened genes present within this interval for mutations. The genes screened included the orthologue of the Sans gene, which is defective in the Jackson shaker deaf mutant and maps to the syntenic region in mice. In two consanguineous USH1G-affected families, we detected two different frameshift mutations in the SANS gene. Two brothers from a German family affected with USH1G were found to be compound heterozygotes for a frameshift and a missense mutation. These results demonstrate that SANS underlies USH1G. The SANS protein contains three ankyrin domains and a sterile alpha motif, and its C-terminal tripeptide presents a class I PDZ-binding motif. We showed, by means of co-transfection experiments, that SANS associates with harmonin, a PDZ domain-containing protein responsible for USH1C. In Jackson shaker mice the hair bundles, the mechanoreceptive structures of inner ear sensory cells, are disorganized. Based on the known interaction between USH1B (myosin VIIa), USH1C (harmonin) and USH1D (cadherin 23) proteins and the results obtained in this study, we suggest that a functional network formed by the USH1B, C, D and G proteins is responsible for the correct cohesion of the hair bundle.

Listen to your gut: Using adhesion to shape the surface of functionally diverse epithelia

“…Parallels between the IMAC and tip-link complex have also allowed exploration of how specific mutations lead to disease in Usher syndrome patients. For example, the L48P substitution associated with Type 1G Usher syndrome impacts a conserved residue in the N-terminal ankyrin repeats of SANS, 48 although the functional effect of this mutation remained unclear. By expressing this mutation in the IMAC functional homolog, ANKS4B, in the context of the CACO-2 BBE intestinal epithelial model system, investigators were able to determine that L48P disrupts targeting of this protein to the apical domain.…”

Hearing molecules: contributions from genetic deafness

“…Another element of the Usher syndrome-related protein complex is SANS (scaffold protein containing ankyrin repeats and SAM domain). SANS was identified in the site of the Usher 1G mutation [37]. SANS has been localized to the apical portion of the hair cell rather than the stereocilia, and interacts with harmonin [37].…”

“…SANS was identified in the site of the Usher 1G mutation [37]. SANS has been localized to the apical portion of the hair cell rather than the stereocilia, and interacts with harmonin [37]. Cadherins CDH23 and PCDH15 form extracellular linkages within the hair bundle.…”

Auditory transduction in the mouse

“…The gene encoding Sans was shown to be mutated in Usher syndrome 1G patients and Jackson shaker mutant mice [43,84]. In Jackson shaker mice, hair bundles are disrupted and mice display cochlear and vestibular defects.…”

“…In Jackson shaker mice, hair bundles are disrupted and mice display cochlear and vestibular defects. In addition to identifying Sans as the mutated protein in Usher syndrome 1G, Weil et al [84] demonstrated that Sans associates with harmonin. Adato et al [1] also probed the possible interactions of Sans with all of the known Usher proteins and demonstrated that, in addition to harmonin, Sans can bind to itself and myosin 7a, tying it into the complex of usher proteins.…”