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

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; Eric A. Pierce; Chris F. Inglehearn

doi:10.1016/j.ajhg.2009.04.005

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

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 BaninTim M. Strom, Debora B. Farber, Dror Sharon, Carl P. Blobel, Edward N. Pugh, Eric A. Pierce, Chris F. Inglehearn^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

67 Scopus citations

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.

Original language	English
Pages (from-to)	683-691
Number of pages	9
Journal	American Journal of Human Genetics
Volume	84
Issue number	5
DOIs	https://doi.org/10.1016/j.ajhg.2009.04.005
State	Published - 15 May 2009
Externally published	Yes

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Parry, D. A., Toomes, C., Bida, L., Danciger, M., Towns, K. V., McKibbin, M., Jacobson, S. G., Logan, C. V., Ali, M., Bond, J., Chance, R., Swendeman, S., Daniele, L. L., Springell, K., Adams, M., Johnson, C. A., Booth, A. P., Jafri, H., Rashid, Y., ... Inglehearn, C. F. (2009). Loss of the Metalloprotease ADAM9 Leads to Cone-Rod Dystrophy in Humans and Retinal Degeneration in Mice. American Journal of Human Genetics, 84(5), 683-691. https://doi.org/10.1016/j.ajhg.2009.04.005

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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.",

author = "Parry, {David A.} and Carmel Toomes and Lina Bida and Michael Danciger and Towns, {Katherine V.} and Martin McKibbin and Jacobson, {Samuel G.} and Logan, {Clare V.} and Manir Ali and Jacquelyn Bond and Rebecca Chance and Steven Swendeman and Daniele, {Lauren L.} and Kelly Springell and Matthew Adams and Johnson, {Colin A.} and Booth, {Adam P.} and Hussain Jafri and Yasmin Rashid and Eyal Banin and Strom, {Tim M.} and Farber, {Debora B.} and Dror Sharon and Blobel, {Carl P.} and Pugh, {Edward N.} and Pierce, {Eric A.} and Inglehearn, {Chris F.}",

year = "2009",

month = may,

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doi = "10.1016/j.ajhg.2009.04.005",

language = "אנגלית",

volume = "84",

pages = "683--691",

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Parry, DA, Toomes, C, Bida, L, Danciger, M, Towns, KV, McKibbin, M, Jacobson, SG, Logan, CV, Ali, M, Bond, J, Chance, R, Swendeman, S, Daniele, LL, Springell, K, Adams, M, Johnson, CA, Booth, AP, Jafri, H, Rashid, Y, Banin, E, Strom, TM, Farber, DB, Sharon, D, Blobel, CP, Pugh, EN, Pierce, EA & Inglehearn, CF 2009, 'Loss of the Metalloprotease ADAM9 Leads to Cone-Rod Dystrophy in Humans and Retinal Degeneration in Mice', American Journal of Human Genetics, vol. 84, no. 5, pp. 683-691. https://doi.org/10.1016/j.ajhg.2009.04.005

TY - JOUR

T1 - Loss of the Metalloprotease ADAM9 Leads to Cone-Rod Dystrophy in Humans and Retinal Degeneration in Mice

AU - Parry, David A.

AU - Toomes, Carmel

AU - Bida, Lina

AU - Danciger, Michael

AU - Towns, Katherine V.

AU - McKibbin, Martin

AU - Jacobson, Samuel G.

AU - Logan, Clare V.

AU - Ali, Manir

AU - Bond, Jacquelyn

AU - Chance, Rebecca

AU - Swendeman, Steven

AU - Daniele, Lauren L.

AU - Springell, Kelly

AU - Adams, Matthew

AU - Johnson, Colin A.

AU - Booth, Adam P.

AU - Jafri, Hussain

AU - Rashid, Yasmin

AU - Banin, Eyal

AU - Strom, Tim M.

AU - Farber, Debora B.

AU - Sharon, Dror

AU - Blobel, Carl P.

AU - Pugh, Edward N.

AU - Pierce, Eric A.

AU - Inglehearn, Chris F.

PY - 2009/5/15

Y1 - 2009/5/15

N2 - 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.

AB - 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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AN - SCOPUS:65149087659

SN - 0002-9297

VL - 84

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EP - 691

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 5

ER -

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

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