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Please use this identifier to cite or link to this item: http://hdl.handle.net/10373/1139

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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
Authors: 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.
Affiliation: University of Abertay Dundee. School of Contemporary Sciences
Keywords: Genetic diseases
Mutation screening
Retinal degeneration
Retinal dystrophy
Retinitis pigmentosa
Knockout animals
Issue Date: Sep-2011
Publisher: Association for Research in Vision and Ophthalmology
Type: Journal Article
Refereed: peer-reviewed
Rights: Published version (c)Association for Research in Vision and Ophthalmology, available from http://dx.doi.org/10.1167/iovs.11-7872 and http://www.iovs.org/content/52/10/7432.full
Citation: Ali, M., et al. 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): pp.7432-7440. Available from http://dx.doi.org/10.1167/iovs.11-7872
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.
URI: http://hdl.handle.net/10373/1139
ISSN: 0146-0404
Appears in Collections:Science Engineering & Technology Collection

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