CH, CH, CH, 1: 2, 1: 2 The Usher syndromes (USHs; MIM 276900–276904, 601067, 60297, and 602083) are a group of autosomal recessive hereditary disorders characterized by the association of sensorineural hearing impairments and progressive visual loss due to retinitis pigmentosa. Three types of USH are distinguished on the basis of severity and onset of auditory and vestibulary dysfunctions. To date, USHs are mapped to nine different genomic loci: USH1A–F, USH2A, USH2B, and USH3 (Hereditary Hearing Loss home page). USH3 (MIM 276902), assigned to chromosome 3q, is regarded as the rarest form of USH (Sankilla et al. 1995) The human myosin VIIA gene (MYO7A), located on 11q14, has been shown to be responsible for USH1B (MIM 276903), which is the most common USH1 subtype, accounting for∼ 75% of all type 1 cases (Weil et al. 1995). More recently, MYO7A has also been shown to be responsible for nonsyndromic recessive and dominant deafness (DFNB2 and DFNA11), both types having been assigned to the same 11q chromosomal region (Liu et al. 1997a, 1997b; Weil et al. 1997). These findings clearly indicate that the enzymatic activity of MYO7A is critical for normal function in the inner ear and that different mutations may cause different dysfunctions that are manifested by distinct phenotypes. Here we report on two novel MYO7A mutations that may have a synergistic effect on the symptoms of another USH different from USH1B. Among USH-affected families recruited as part of a study on the genetics of USH, results of which were published in this journal (Adato et al. 1997), was a nonconsanguineous family of Jewish Yemenite origin that included two affected and six healthy siblings. The two affected brothers in this family have different USH phenotypes. One of the affected brothers (1549 in fig. 1) has a typical USH1 phenotype: he has a history of prelingual profound auditory impairment; he uses sign language for communication, since hearing aids are unhelpful in his case; and developmental milestones (Smith et al. 1994) in his childhood are consistent with congenital vestibular dysfunction. The other affected brother (1636 in fig. 1) has a typical USH3 phenotype: he has progressive hearing loss, with postlingual onset; he uses hearing aids and verbal communication; and he receives psychiatric therapy for mental problems. In both affected brothers, the presence of bilateral progressive pigmentary retinopathy has been diagnosed (with onset during early adolescence).

Members of this family were typed for 30 polymorphic markers spanning all nine known USH loci (USH1A-F, USH2A, USH2B, and USH3). Marker alleles were identified and arranged into the most likely haplotypes, as shown in figure 1. Haplotype segregation and linkage analysis resulted in exclusion of all USH1 and USH2 loci (LOD scores range from 1.46 to 3.72) and suggested linkage only to the USH3 locus (with a maximum LOD score of 1.35 for marker D3S1279). Both affected brothers showed homozygosity for alleles of four markers: D3S1315, D3S1279, D3S3625, and D3S1294. Homozygosity of USH3 haplotypes in the affected brothers—and the fact that, although not known to be related, both parents originate from a small Jewish community in Yemen—suggest a possible common origin for both USH3-bearing chromosomes. This “USH3 haplotype” was found to be carried (one copy) by only 2 of 54 Jewish Yemenite control subjects tested for its presence. The homozygote interval in both affected brothers and the position of recombination in the paternal chromosome of one healthy progeny (1643; see fig. 1) suggest that the USH3 gene is …