Mpdz null allele in an avian model of retinal degeneration and mutations in human leber congenital amaurosis and retinitis pigmentosa

Manir Ali, Paul M. Hocking, Martin McKibbin, Sorcha Finnegan, Mike Shires, James A. Poulter, Katrina Prescott, Adam Booth, Yasmin Raashid, Hussain Jafri, Jonathan B. Ruddle, David A. Mackey, Samuel G. Jacobson, Carmel Toomes, Douglas H. Lester, David W. Burt, William J. Curry, Chris F. Inglehearn

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Abstract

Purpose. To identify the defective gene in the sex-linked, recessively inherited retinal dysplasia and degeneration (rdd) chicken and to search for the human equivalent disease. Methods. Microsatellites from chicken chromosome Z were genotyped in 77 progeny of a carrier male (rdd/+) and an affected female (rdd/W), and candidate genes were sequenced. Retinal cross-sections from rdd and wild-type birds were analyzed by immunohistology. The human orthologous gene was screened in a panel of archival DNAs from 276 patients with retinitis pigmentosa (RP) or Leber congenital amaurosis (LCA) using melting curve analysis and DNA sequencing. Results. The rdd locus was refined to an approximately 3-Mb region on chromosome Z. Sequence analysis identified a C→T change in the mpdz gene that created a premature stop codon (c.1372C→T, p.R458X), which segregated with the disease phenotype. As expected, the full-length mpdz protein was absent in rdd retinas, but in wild-type birds, it localized to the retinal outer limiting membrane, where it may have a role in the interactions between photoreceptors and Müller glia cells. The screen to identify the human equivalent disease found 10 heterozygous variants in the orthologous gene in patients with RP (three missense and two null alleles) and LCA (four missense and one null allele). Conclusions. These findings reveal that MPDZ is essential for normal development of the retina and may have a role in maintaining photoreceptor integrity. The identification of human mutations suggests that MPDZ plays a role in human retinal disease, but the precise nature of this role remains to be determined.
Original languageEnglish
Pages (from-to)7432-7440
Number of pages9
JournalInvestigative Ophthalmology & Visual Science
Volume52
Issue number10
DOIs
StatePublished - Sep 2011

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Retinal Dysplasia
Leber Congenital Amaurosis
Retinal Degeneration
Retinitis Pigmentosa
Alleles
Mutation
Genes
Birds
Retina
Chickens
Chromosomes
Retinal Diseases
Forensic Anthropology
Nonsense Codon
DNA Sequence Analysis
Neuroglia
Microsatellite Repeats
Freezing
Sequence Analysis
Phenotype

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Ali, M., Hocking, P. M., McKibbin, M., Finnegan, S., Shires, M., Poulter, J. A., ... Inglehearn, C. F. (2011). Mpdz null allele in an avian model of retinal degeneration and mutations in human leber congenital amaurosis and retinitis pigmentosa. Investigative Ophthalmology & Visual Science, 52(10), 7432-7440. DOI: 10.1167/iovs.11-7872

Ali, Manir; Hocking, Paul M.; McKibbin, Martin; Finnegan, Sorcha; Shires, Mike; Poulter, James A.; Prescott, Katrina; Booth, Adam; Raashid, Yasmin; Jafri, Hussain; Ruddle, Jonathan B.; Mackey, David A.; Jacobson, Samuel G.; Toomes, Carmel; Lester, Douglas H.; Burt, David W.; Curry, William J.; Inglehearn, Chris F. / Mpdz null allele in an avian model of retinal degeneration and mutations in human leber congenital amaurosis and retinitis pigmentosa.

In: Investigative Ophthalmology & Visual Science, Vol. 52, No. 10, 09.2011, p. 7432-7440.

Research output: Contribution to journalArticle

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title = "Mpdz null allele in an avian model of retinal degeneration and mutations in human leber congenital amaurosis and retinitis pigmentosa",
abstract = "Purpose. To identify the defective gene in the sex-linked, recessively inherited retinal dysplasia and degeneration (rdd) chicken and to search for the human equivalent disease. Methods. Microsatellites from chicken chromosome Z were genotyped in 77 progeny of a carrier male (rdd/+) and an affected female (rdd/W), and candidate genes were sequenced. Retinal cross-sections from rdd and wild-type birds were analyzed by immunohistology. The human orthologous gene was screened in a panel of archival DNAs from 276 patients with retinitis pigmentosa (RP) or Leber congenital amaurosis (LCA) using melting curve analysis and DNA sequencing. Results. The rdd locus was refined to an approximately 3-Mb region on chromosome Z. Sequence analysis identified a C→T change in the mpdz gene that created a premature stop codon (c.1372C→T, p.R458X), which segregated with the disease phenotype. As expected, the full-length mpdz protein was absent in rdd retinas, but in wild-type birds, it localized to the retinal outer limiting membrane, where it may have a role in the interactions between photoreceptors and Müller glia cells. The screen to identify the human equivalent disease found 10 heterozygous variants in the orthologous gene in patients with RP (three missense and two null alleles) and LCA (four missense and one null allele). Conclusions. These findings reveal that MPDZ is essential for normal development of the retina and may have a role in maintaining photoreceptor integrity. The identification of human mutations suggests that MPDZ plays a role in human retinal disease, but the precise nature of this role remains to be determined.",
author = "Manir Ali and Hocking, {Paul M.} and Martin McKibbin and Sorcha Finnegan and Mike Shires and Poulter, {James A.} and Katrina Prescott and Adam Booth and Yasmin Raashid and Hussain Jafri and Ruddle, {Jonathan B.} and Mackey, {David A.} and Jacobson, {Samuel G.} and Carmel Toomes and Lester, {Douglas H.} and Burt, {David W.} and Curry, {William J.} and Inglehearn, {Chris F.}",
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Ali, M, Hocking, PM, McKibbin, M, Finnegan, S, Shires, M, Poulter, JA, Prescott, K, Booth, A, Raashid, Y, Jafri, H, Ruddle, JB, Mackey, DA, Jacobson, SG, Toomes, C, Lester, DH, Burt, DW, Curry, WJ & Inglehearn, CF 2011, 'Mpdz null allele in an avian model of retinal degeneration and mutations in human leber congenital amaurosis and retinitis pigmentosa' Investigative Ophthalmology & Visual Science, vol 52, no. 10, pp. 7432-7440. DOI: 10.1167/iovs.11-7872

Mpdz null allele in an avian model of retinal degeneration and mutations in human leber congenital amaurosis and retinitis pigmentosa. / Ali, Manir; Hocking, Paul M.; McKibbin, Martin; Finnegan, Sorcha; Shires, Mike; Poulter, James A.; Prescott, Katrina; Booth, Adam; Raashid, Yasmin; Jafri, Hussain; Ruddle, Jonathan B.; Mackey, David A.; Jacobson, Samuel G.; Toomes, Carmel; Lester, Douglas H.; Burt, David W.; Curry, William J.; Inglehearn, Chris F.

In: Investigative Ophthalmology & Visual Science, Vol. 52, No. 10, 09.2011, p. 7432-7440.

Research output: Contribution to journalArticle

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T1 - Mpdz null allele in an avian model of retinal degeneration and mutations in human leber congenital amaurosis and retinitis pigmentosa

AU - Ali,Manir

AU - Hocking,Paul M.

AU - McKibbin,Martin

AU - Finnegan,Sorcha

AU - Shires,Mike

AU - Poulter,James A.

AU - Prescott,Katrina

AU - Booth,Adam

AU - Raashid,Yasmin

AU - Jafri,Hussain

AU - Ruddle,Jonathan B.

AU - Mackey,David A.

AU - Jacobson,Samuel G.

AU - Toomes,Carmel

AU - Lester,Douglas H.

AU - Burt,David W.

AU - Curry,William J.

AU - Inglehearn,Chris F.

PY - 2011/9

Y1 - 2011/9

N2 - Purpose. To identify the defective gene in the sex-linked, recessively inherited retinal dysplasia and degeneration (rdd) chicken and to search for the human equivalent disease. Methods. Microsatellites from chicken chromosome Z were genotyped in 77 progeny of a carrier male (rdd/+) and an affected female (rdd/W), and candidate genes were sequenced. Retinal cross-sections from rdd and wild-type birds were analyzed by immunohistology. The human orthologous gene was screened in a panel of archival DNAs from 276 patients with retinitis pigmentosa (RP) or Leber congenital amaurosis (LCA) using melting curve analysis and DNA sequencing. Results. The rdd locus was refined to an approximately 3-Mb region on chromosome Z. Sequence analysis identified a C→T change in the mpdz gene that created a premature stop codon (c.1372C→T, p.R458X), which segregated with the disease phenotype. As expected, the full-length mpdz protein was absent in rdd retinas, but in wild-type birds, it localized to the retinal outer limiting membrane, where it may have a role in the interactions between photoreceptors and Müller glia cells. The screen to identify the human equivalent disease found 10 heterozygous variants in the orthologous gene in patients with RP (three missense and two null alleles) and LCA (four missense and one null allele). Conclusions. These findings reveal that MPDZ is essential for normal development of the retina and may have a role in maintaining photoreceptor integrity. The identification of human mutations suggests that MPDZ plays a role in human retinal disease, but the precise nature of this role remains to be determined.

AB - Purpose. To identify the defective gene in the sex-linked, recessively inherited retinal dysplasia and degeneration (rdd) chicken and to search for the human equivalent disease. Methods. Microsatellites from chicken chromosome Z were genotyped in 77 progeny of a carrier male (rdd/+) and an affected female (rdd/W), and candidate genes were sequenced. Retinal cross-sections from rdd and wild-type birds were analyzed by immunohistology. The human orthologous gene was screened in a panel of archival DNAs from 276 patients with retinitis pigmentosa (RP) or Leber congenital amaurosis (LCA) using melting curve analysis and DNA sequencing. Results. The rdd locus was refined to an approximately 3-Mb region on chromosome Z. Sequence analysis identified a C→T change in the mpdz gene that created a premature stop codon (c.1372C→T, p.R458X), which segregated with the disease phenotype. As expected, the full-length mpdz protein was absent in rdd retinas, but in wild-type birds, it localized to the retinal outer limiting membrane, where it may have a role in the interactions between photoreceptors and Müller glia cells. The screen to identify the human equivalent disease found 10 heterozygous variants in the orthologous gene in patients with RP (three missense and two null alleles) and LCA (four missense and one null allele). Conclusions. These findings reveal that MPDZ is essential for normal development of the retina and may have a role in maintaining photoreceptor integrity. The identification of human mutations suggests that MPDZ plays a role in human retinal disease, but the precise nature of this role remains to be determined.

U2 - 10.1167/iovs.11-7872

DO - 10.1167/iovs.11-7872

M3 - Article

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SP - 7432

EP - 7440

JO - Investigative Ophthalmology & Visual Science

T2 - Investigative Ophthalmology & Visual Science

JF - Investigative Ophthalmology & Visual Science

SN - 0146-0404

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