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.

NovelADAM9homozygous mutation in a consanguineous Egyptian family with severe cone-rod dystrophy and cataract

“…Danciger et al described a ‘small’ posterior subcapsular cataract in the large Brazilian family 11. This observation was not described in a more recent article which included three other families with ADAM9 arCRD 6. In our study, the mother presented with an anterior polar and a posterior subcapsular cataract, but the two children affected by CRD did not, whereas three children out of the four unaffected by CRD showed dot cataract.…”

“…Although mutations in ABCA4 are found in 24–65% of arCRD,1 3 8–10 many patients remain without molecular diagnosis. In 2009, Parry et al 6 observed that mutations in the ADAM metallopeptidase domain 9 ( ADAM9 ) gene were responsible for the arCRD observed in a Brazilian family first described and mapped under CORD9 by Danciger et al in 2001 11…”

Mutations in MFSD8, Encoding a Lysosomal Membrane Protein, Are Associated with Nonsyndromic Autosomal Recessive Macular Dystrophy

“…Three of these genes initially have been associated with ACHM, a form of cone dysfunction that can develop into COD. Eighteen genes have been associated with ar CRD (ABCA4, 17 ADAM9, 18 C8orf37, 19 CDHR1, 20,21 CERKL, 22 CNGB3, 23 CRB1, 24 CRX, 24 EYS, 25 FSCN2, 26 GUCY2D, 27 KCNV2, 14 PDE6C, 23 POC1B, 28,29 PROM1, 30 RAB28, 31 RPE65, 24 RPGRIP1, 23 and TULP1 16 ). In both disorders, mutations in these genes explain disease in an estimated 21% (COD) and 25% (CRD) of patients.…”

A novelC8orf37splice mutation and genotype-phenotype correlation for cone-rod dystrophy

“…The regions encompass a total of 190 refseq genes. 11 Of the six arCRD causative genes known to date (ABCA4, 12 ADAM9, 13 C8orf37, 1 CERKL, 14 RPGRIP1, 15 and CDHR1 16 ), C8orf37 was the only one included in a homozygous interval. Since the phenotype in both affected siblings was consistent with the diagnosis of CRD, C8orf37 appeared to be the best candidate gene in this family.…”