Usher Syndrome, Type Ig

A number sign (#) is used with this entry because Usher syndrome type IG can be caused by homozygous or compound heterozygous mutation in the SANS gene (USH1G; 607696) on chromosome 17q25.

For a discussion of genetic heterogeneity of Usher syndrome type I, see 276900.

Description

Usher syndrome is an autosomal recessive disorder associated with sensorineural hearing impairment and progressive visual loss attributable to retinitis pigmentosa. The syndrome is both clinically and genetically heterogeneous. Of the 3 different clinical types that have been described, USH1 (276900), consisting of the association of profound congenital deafness, constant vestibular dysfunction, and prepubertal onset retinitis pigmentosa, is the most severe.

Clinical Features

Bashir et al. (2010) reported 4 affected members of a consanguineous Pakistani family with Usher syndrome type IG. The patients had an atypical form of the disorder, 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.

Mapping

Using linkage analysis, Mustapha et al. (2002) identified a novel USH1 locus, which they designated USH1G, in a consanguineous Palestinian family living in Jordan with 3 affected children. Linkage had excluded the involvement of any of the known USH1 loci. Genomewide screening mapped the USH1G locus to a 23-cM interval on 17q24-q25. The USH1G interval overlaps the interval for a dominant form of isolated hearing loss, DFNA20 (604717). Since several examples of syndromic and isolated forms of deafness being allelic had been reported, Mustapha et al. (2002) suggested that USH1G and DFNA20 might be allelic.

Molecular Genetics

In affected members of Tunisian, German, and Jordanian families segregating Usher syndrome type IG, Weil et al. (2003) identified mutations in the SANS gene (607696.0001-607696.0004).

In 4 affected members of a consanguineous Pakistani family with a mild form of Usher syndrome type IG, 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 (607696.0006). 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 findings indicated that even a truncating mutation in the USH1G gene can result in a relatively mild phenotype.

Animal Model

The Jackson shaker (js) 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.