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To determine the molecular cause of sector retinitis pigmentosa and hearing loss in two affected siblings.Direct DNA sequencing of the USH1C gene was performed in two affected siblings. Putative pathogenic sequence changes were assayed in their parent's chromosomes and in control chromosomes. Clinical examination included visual acuity measurement, visual field measurement, electrophysiologic assessment, and fine matrix mapping. Retinal imaging with fundus photography, scanning laser ophthalmoscope (fundus autofluorescence), and optical coherence tomography was performed. Hearing and vestibular function was also assessed.The siblings were aged 42 years and 40 years, and both were compound heterozygotes for the p.R103H missense change and the novel splice site change c.2227-1GA in the USH1C gene. Both alleles were found to be in trans. Neither allele was identified in a panel of 866 control chromosomes, and both were considered pathogenic. Both siblings had sector retinitis pigmentosa restricted to the inferior and nasal retina. Fundus autofluorescence imaging showed a clear demarcation between normal and abnormal areas of retina, which corresponded to areas of reduced sensitivity on fine matrix mapping and loss of visual field. Both siblings had severe hearing loss but were able to develop language.We report a novel molecular cause of sector retinitis pigmentosa associated with hearing loss representing a new phenotype associated with mutations in the USH1C gene.

Purpose of reviewThe present review addresses the mechanisms, genetics and pathogenesis of Usher syndrome.Recent findingsRecent molecular findings have provided more information regarding the pathogenesis of this disorder and the wide phenotypic variation in both audiovestibular and/or visual systems. Evidence has begun to emerge supporting a theory of a protein interactome involving the Usher proteins in both the inner ear and the retina. This interactome appears to be important for hair cell development in the ear but its role in the retina remains unclear.SummaryUnderstanding clinical disease progression and molecular pathways is important in the progress towards developing gene therapy to prevent blindness due to Usher syndrome as well as delivering prognostic information to affected individuals.

To The Editor: Li et al1 propose that 2 new mutations in KVLQT1 in Romano-Ward syndrome (RWS) disrupt splicing, leading to frameshift and premature protein truncation, acting through a loss-of-function mechanism. This is surprising because missense mutations in KVLQT1, acting in a dominant-negative manner, predominate in RWS. In Table 2 of the article by Li et al, 24 of the 26 mutations are missense (the 2 remaining being discussed here). We suggest alternative interpretations. The SP/A249/g-a mutation …