title: Loss of the metalloprotease ADAM9 leads to cone-rod dystrophy in humans and retinal degeneration in mice.
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.
authors.affiliation: Section of Ophthalmology and Neuroscience, Leeds Institute of Molecular Medicine, St. James's University Hospital, Leeds LS9 7TF, UK.
authors.forename: David A
authors.initials: DA
authors.lastname: Parry
authors.forename: Carmel
authors.initials: C
authors.lastname: Toomes
authors.forename: Lina
authors.initials: L
authors.lastname: Bida
authors.forename: Michael
authors.initials: M
authors.lastname: Danciger
authors.forename: Katherine V
authors.initials: KV
authors.lastname: Towns
authors.forename: Martin
authors.initials: M
authors.lastname: McKibbin
authors.forename: Samuel G
authors.initials: SG
authors.lastname: Jacobson
authors.forename: Clare V
authors.initials: CV
authors.lastname: Logan
authors.forename: Manir
authors.initials: M
authors.lastname: Ali
authors.forename: Jacquelyn
authors.initials: J
authors.lastname: Bond
authors.forename: Rebecca
authors.initials: R
authors.lastname: Chance
authors.forename: Steven
authors.initials: S
authors.lastname: Swendeman
authors.forename: Lauren L
authors.initials: LL
authors.lastname: Daniele
authors.forename: Kelly
authors.initials: K
authors.lastname: Springell
authors.forename: Matthew
authors.initials: M
authors.lastname: Adams
authors.forename: Colin A
authors.initials: CA
authors.lastname: Johnson
authors.forename: Adam P
authors.initials: AP
authors.lastname: Booth
authors.forename: Hussain
authors.initials: H
authors.lastname: Jafri
authors.forename: Yasmin
authors.initials: Y
authors.lastname: Rashid
authors.forename: Eyal
authors.initials: E
authors.lastname: Banin
authors.forename: Tim M
authors.initials: TM
authors.lastname: Strom
authors.forename: Debora B
authors.initials: DB
authors.lastname: Farber
authors.forename: Dror
authors.initials: D
authors.lastname: Sharon
authors.forename: Carl P
authors.initials: CP
authors.lastname: Blobel
authors.forename: Edward N
authors.initials: EN
authors.lastname: Pugh
authors.forename: Eric A
authors.initials: EA
authors.lastname: Pierce
authors.forename: Chris F
authors.initials: CF
authors.lastname: Inglehearn
mesh_terms: D051722:ADAM Proteins / Q000235:genetics*; D000818:Animals; D003241:Consanguinity; D020022:Genetic Predisposition to Disease; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D010375:Pedigree; D020419:Photoreceptor Cells, Vertebrate / Q000473:pathology; D012162:Retinal Degeneration / Q000235:genetics* / Q000473:pathology; D055213:Retinal Pigment Epithelium / Q000473:pathology; D012174:Retinitis Pigmentosa / Q000235:genetics*
chemical_list: D008565:Membrane Proteins; D051722:ADAM Proteins; C098339:ADAM9 protein, human; C498316:Adam9 protein, mouse