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Loss of the Metalloprotease ADAM9 Leads to Cone-Rod Dystrophy in Humans and Retinal Degeneration in Mice |
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| Authors: | David A. Parry Lina Bida Katherine V. Towns Samuel G. Jacobson Manir Ali Rebecca Chance Lauren L. Daniele Matthew Adams Adam P. Booth Yasmin Rashid Tim M. Strom Dror Sharon Edward N. Pugh Jr. Chris F. Inglehearn |
| Affiliation: | 1 Section of Ophthalmology and Neuroscience, Leeds Institute of Molecular Medicine, St. James's University Hospital, Leeds LS9 7TF, UK 2 Department of Ophthalmology, Hadassah-Hebrew University Medical Center, 91120 Jerusalem, Israel 3 Loyola Marymount University, Los Angeles, CA 90045, USA 4 Eye Department, Chancellor Wing, St James's University Hospital, Leeds LS9 7TF, UK 5 F.M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA 6 Hopsital for Special Surgery at Weill Medical College of Cornell University, New York, NY 10021, USA 7 Peninsula Medical School, Plymouth PL6 8BU, UK 8 Gene Tech Lab 146/1, Shadman Jail Road, Lahore, 54000, Pakistan 9 Department of Obstetrics and Gynaecology, King Edward Medical University, Lahore, 54000, Pakistan 10 Institute of Human Genetics, Helmholtz Zentrum München, German Research Centre for Environmental Health, 85764 Neuherberg, Germany 11 Jules Stein Eye Institute, UCLA School of Medicine, Los Angeles, CA 90095, USA |
| Abstract: | Cone-rod dystrophy (CRD) is an inherited progressive retinal dystrophy affecting the function of cone and rod photoreceptors. By autozygosity mapping, we identified null mutations in the ADAM metallopeptidase domain 9 (ADAM9) gene in four consanguineous families with recessively inherited early-onset CRD. We also found reduced photoreceptor responses in Adam9 knockout mice, previously reported to be asymptomatic. In 12-month-old knockout mice, photoreceptors appear normal, but the apical processes of the retinal pigment epithelium (RPE) cells are disorganized and contact between photoreceptor outer segments (POSs) and the RPE apical surface is compromised. In 20-month-old mice, there is clear evidence of progressive retinal degeneration with disorganized POS and thinning of the outer nuclear layer (ONL) in addition to the anomaly at the POS-RPE junction. RPE basal deposits and macrophages were also apparent in older mice. These findings therefore not only identify ADAM9 as a CRD gene but also identify a form of pathology wherein retinal disease first manifests at the POS-RPE junction. |
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