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H. J. Bolz, H. P. N. Scholl, P. Charbel Issa, E. Becirovic, Jü. Lamprecht, B. Jurklies, J. M. Millán, E. Aller, D. Mitter, I. Ebermann; A Novel Gene for Usher Syndrome Type 2 (USH2D): Mutations in the Long Isoform of Whirlin Are Associated With Retinitis Pigmentosa and Sensorineural Hearing Loss. Invest. Ophthalmol. Vis. Sci. 2007;48(13):6000.
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To identify the causative mutation in a German USH2 family unlinked to known gene loci for Usher syndrome.
Patients underwent detailed ophthalmological and audiological investigations. The seven proteins that have been identified for Usher syndrome type 1 (USH1) and type 2 (USH2) interact in a large protein complex. We assumed that mutations in proteins interacting with this "USH network" may cause Usher syndrome as well. DFNB31 encodes whirlin, a PDZ scaffold protein with expression in both hair cell stereocilia and retinal photoreceptor cells. Whirlin binds to Usherin (USH2A) and VLGR1b (USH2C). Genotyping of microsatellite markers specific for the known USH loci and the DFNB31 gene locus on chromosome 9q32 and direct sequencing was performed.
Two individuals in the family investigated herein are affected by USH2. Hearing loss is mild in the younger patient and moderate in the older sister. Both individuals exhibited a phenotype of a rod-cone dystrophy with preserved visual acuity, concentric visual field loss, and typical intraretinal pigment clumping in the mid periphery. Mutations in known USH genes could be excluded by linkage analysis and direct sequencing. Patients showed common haplotypes for the DFNB31 locus. Sequence analysis of DFNB31 revealed compound heterozygosity for a nonsense mutation, p.Q103X, in exon 1, and a mutation in the splice donor site of exon 2, c.837+1G>A. No mutations were identified in an additional 96 USH2 patients.
We describe a novel genetic subtype for Usher syndrome, which we named USH2D and which is caused by mutations in whirlin. Moreover, this is the first case of USH2 that is allelic to non-syndromic deafness. While mutations in the C-terminal half of whirlin have previously been reported in non-syndromic deafness (DFNB31), both alterations identified in our USH2 family affect the long protein isoform. We propose that mutations causing Usher syndrome are probably restricted to exons 1 - 6 that are specific for the long isoform and probably crucial for retinal function. DFNB31 mutations appear to be a rare cause of Usher syndrome.
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