Mouse model for Usher syndrome: linkage mapping suggests homology to Usher type I reported at human chromosome 11p15.

Abstract

Usher syndrome is a group of diseases with autosomal recessive inheritance, congenital hearing loss, and the development of retinitis pigmentosa, a progressive retinal degeneration characterized by night blindness and visual field loss over several decades. The causes of Usher syndrome are unknown and no animal models have been available for study. Four human gene sites have been reported, suggesting at least four separate forms of Usher syndrome. We report a mouse model of type I Usher syndrome, rd5, whose linkage on mouse chromosome 7 to Hbb and tub has homology to human Usher I reported on human chromosome lipl5. The electroretinogram in homozygous rd5/rd5 mouse is never normal with reduced amplitudes that extinguish by 6 months. Auditoryevoked response testing demonstrates increased hearing thresholds more than control at 3 weeks of about 30 decibels (dB) that worsen to about 45 dB by 6 months.Usher syndrome is the most common retinitis pigmentosa syndrome. The incidence in the general population is estimated to be 4.4 per 100,000, and within the deaf population, the prevalence rate has been reported to range from 3% to 6% (1-3). There are two clinical forms of Usher syndrome: types I and II. Type I patients have congenital profound hearing loss with auditory thresholds typically >100 decibels (dB) and marked hypoactivity of vestibular function (4, 5). There are three human gene linkage sites reported for Usher type I, chromosomes liplS (6), 11q14 (7), and 14q32 (8) stimuli repetitions were averaged to obtain threshold values, by decreasing the intensity by 10-dB intervals to subthreshold and then by increasing or decreasing the intensity by 5-dB intervals until repeated waveforms for at least two peaks were identified. Normal controls were 6-month-old C57BL/6J mice.Electroretinography and Indirect Ophthalmoscopy. Electroretinograms were performed as reported (17,19). A range of intensity flash levels over four orders of magnitude with a Grass photostimulator and neutral density filters (Kodak) was used to evoke the electroretinogram. For the natural history study, a 10-,tsec single flash intensity (73 foot-lamberts-sec; 1 footlambert = 3.426 cd/mi2) was used to follow the retinal degeneration. Indirect ophthalmoscopy was performed by using a 40-or 60-diopter aspheric lens and retinal biomicroscopy was performed by using a 90-diopter lens.Histology. Light microscopic examination was performed on 15 eyes, ages 3, 4, 6, 7, 8, 10, 11, 18, and 24 weeks, which were enucleated immediately after anesthetic overdose with Avertin and immersed in ice-cold fixative [1% paraformaldehyde/2% (vol/vol) glutaldehyde/0.1 M cacodylate buffer, pH 7.4] for 24 h, embedded in hydroxyethylmethacrylate, and sectioned along the temporal-nasal axis.For ultrastructural studies, eyes from rd5/rd5 mutants at 3, 5, 7, 9, and 11 postnatal weeks old were fixed with 0.5x Karnovsky's fixative (pH 7.4) for 24 h, rinsed in 100 mM sodium cacodylate buffer (pH 7.4), and fixed secondarily in 2.0% (wt/vol) osmium tetroxide for 1-2 h. T...

Insulin Receptor Substrate 2 Is Essential for Maturation and Survival of Photoreceptor Cells

“…Bardet-Biedl syndrome is characterized by many systemic disorders, including retinal dystrophy or pigmentary retinopathy, which is accompanied by abdominal obesity and type 2 diabetes (Iannello et al, 2002). Mutations in the Tubby gene family reveal a relationship between retinal function and insulin action (Ikeda et al, 2002); mutations in the mouse Tubby gene causes obesity, deafness, and retinal photoreceptor degeneration (Heckenlively et al, 1995). In addition, mutations in tubby-like protein 1 (TULP1), a member of the human Tubby gene family, are associated with autosomal recessive retinitis pigmentosa (Banerjee et al, 1998;Hagstrom et al, 1998).…”

Morphological characterization of the retinal degeneration in three strains of mice carrying the rd-3 mutation

“…It is caused by an autosomal recessive gene on chromosome 1, at a totally different locus than the genes associated with the rd~Carter- Dawson et al, 1978!, Rds Sanyal et al, 1980!, pcd, nr~Mullen & LaVail, 1975!, mnd Chang et al, 1994!, tubby~Heckenlively et al, 1995Lamoreux et al, 1992!, rd6~Hawes et al, 2000 Mehalow et al, 2003!, or Rpe65 rd12~P ang et al, 2005generations in mice. Crossbreeding of rd-3/rd-3 mice with mice homozygous for the first six of these mutations produce unaffected offspring~Chang et al, 1993aoffspring~Chang et al, , 1994Heckenlively et al, 1995!. Preliminary studies using both morphological and electroretinogram~ERG! data showed a strong correlation between the time course of photoreceptor loss in each strain and the gradual extinction of the a-wave in each~Chang et al, 1993a; Heckenlively et al, 1993b; Nusinowitz et al, 1997!.…”

Contig Maps and Genomic Sequencing Identify Candidate Genes in the Usher 1C Locus

“…The tubby and rd5 mouse phenotypes display both retinal and cochlear degeneration and have been suggested as murine models for Usher syndrome, as these mutations map to distal mouse chromosome 7, which is partially syntenic to 11p15 (Heckenlively et al 1995;Ohlemiller et al 1995;Chung et al 1996). However, based on both genetic and physical mapping studies, a relationship with USH1C seems unlikely.…”