Loss of the Metalloprotease ADAM9 Leads to Cone-rod Dystrophy in Humans and Retinal Degeneration in Mice

Overview

Journal Am J Hum Genet

Publisher Cell Press

Specialty Genetics

Date 2009 May 5

PMID 19409519

Citations 43

Authors

David A Parry

Carmel Toomes

Lina Bida

Michael Danciger

Katherine V Towns

Martin McKibbin

Samuel G Jacobson

Clare V Logan

Manir Ali

Jacquelyn Bond

Rebecca Chance

Steven Swendeman

Lauren L Daniele

Kelly Springell

Matthew Adams

Colin A Johnson

Adam P Booth

Hussain Jafri

Yasmin Rashid

Eyal Banin

Tim M Strom

Debora B Farber

Dror Sharon

Carl P Blobel

Edward N Pugh Jr

Eric A Pierce

Chris F Inglehearn

Affiliations

Soon will be listed here.

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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