USH2 is known to account for more than half of the Usher syndromes. USH2 could be easily distinguished from USH1 by the severity and audiometric configuration of the hearing loss and by the preserved vestibular function. USH2 is characterized by moderate to severe sensorineural hearing loss with a high frequency sloping configuration. Vestibular response to a caloric stimulus is typically normal. By contrast, the audiograms in USH1 show no detectable hearing across all frequencies, although there may be some residual hearing at the low frequencies.
The
USH2A (OMIM 608400) is located in 1q41 and was first described as comprising 21 exons over 259 kb of genomic DNA [
6]. However, in up to 40 to 70% of patients with USH2, only a single mutation was detected in these 21 exons of the
USH2A gene [
7]. The existence of additional exons, suggested by the presence of larger transcripts, was confirmed in 2004 when van Wijk et al. [
8] identified 51 novel exons at the 3'-end of the
USH2A. A long open reading frame extends from exon 2 to 72, encoding a putative protein of 5,202 amino acids. The functional significance of the long isoform of the
USH2A was shown by the presence of pathological mutations in several of the 51 novel exons in patients with USH2. Up to date, more than 70 different mutations of
USH2A have been reported in patients with USH2 from various ethnicities, with some founder mutations [
9]. Small deletion mutations account for ~26% of all mutations reported. In the present study, we identified a novel small deletion mutation in exon 13 of
USH2A (c.2310delA; p.Glu771LysfsX17). We speculate that the frameshift transcripts from the mutant allele in the patient were subjected to nonsense-mediated mRNA decay, leading to a deficiency of USH2A protein, and thereby, the disease phenotype. Of note, we could found only one mutation, suggesting the presence of the other mutation that cannot be detected on direct sequencing, even involving all coding exons and flanking sequences. Baux et al. identified 34 distinct mutations in the
USH2A in affected individuals from 25 families with USH2, using the same molecular genetic technique as in our patient. They observed one patient who was homozygous for a mutation, 22 who were compound heterozygous for two different mutations, and 2 patients (8%) who were heterozygous for only one mutation [
10]. This study, along with our patient described herein, suggests that there would be other types of
USH2A mutations that cannot be detected by direct sequencing. The possibilities include mutations occurring in the promoter region, other intronic regions, or in the 3'- or 5'-untranslated region. Large genomic rearrangement mutations (deletion or insertion/duplication) can also be considered. Indeed, one patient in the Baux et al.'s series had a large deletion mutation involving at least exon 22, confirmed by semiquantitative PCR [
10]. Recent studies suggest that USH2A protein is integrated into a protein network formed by other USH-causing proteins [
11]. Therefore, another possibility could be that the other mutation might lie in an exon that has not been characterized yet. Finding the other mutation underlying the disease in such patients will give a new insight into the molecular pathogenesis of USH.