Loss of the metalloprotease ADAM9 leads to cone-rod dystrophy in humans and retinal degeneration in mice.
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.
Parry
David A
DA
Section of Ophthalmology and Neuroscience, Leeds Institute of Molecular Medicine, St. James's University Hospital, Leeds LS9 7TF, UK.
Toomes
Carmel
C
Bida
Lina
L
Danciger
Michael
M
Towns
Katherine V
KV
McKibbin
Martin
M
Jacobson
Samuel G
SG
Logan
Clare V
CV
Ali
Manir
M
Bond
Jacquelyn
J
Chance
Rebecca
R
Swendeman
Steven
S
Daniele
Lauren L
LL
Springell
Kelly
K
Adams
Matthew
M
Johnson
Colin A
CA
Booth
Adam P
AP
Jafri
Hussain
H
Rashid
Yasmin
Y
Banin
Eyal
E
Strom
Tim M
TM
Farber
Debora B
DB
Sharon
Dror
D
Blobel
Carl P
CP
Pugh
Edward N
EN
Pierce
Eric A
EA
Inglehearn
Chris F
CF
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*
D008565:Membrane Proteins; D051722:ADAM Proteins; C098339:ADAM9 protein, human; C498316:Adam9 protein, mouse