-
[show abstract]
[hide abstract]
ABSTRACT: OBJECTIVE: To investigate qualitative and quantitative differences in the structure of the posterior segment of the eye in 1-day post-hatch and 12-month-old retinal dysplasia and degeneration (rdd) and wild-type chickens. ANIMAL STUDIED: Retinal dysplasia and degeneration and wild-type chickens. PROCEDURE: Using a commercially available spectral domain optical coherence tomography (OCT) system, 15° horizontal line scans were performed in both eyes of 24 live birds. Qualitative differences in retinal lamination and choroidal structure were investigated, and retinal and choroidal thickness were measured. RESULTS: Progressive retinal thinning with loss of outer retinal lamination and changes in the appearance of the choroid were seen in the rdd birds. Mean total retinal thickness was 202 μm (SD 7.8) and 251 μm (SD 8.8) in the rdd and wild-type chicks and 154 μm (SD 18) and 280 μm (SD 10.8) in the adult birds. Much of the difference was the result of loss of outer retinal lamination and thickness in the rdd birds. Mean choroidal thickness was 76 μm (SD 19.6) and 112 μm (SD 36.9) in the rdd and wild-type chicks and 85 μm (SD 23.7) and 228 μm (SD 44.1) in the rdd and wild-type adult birds, respectively. CONCLUSIONS: Differences in retinal and choroidal structure and thickness between rdd and wild-type birds were evident on spectral domain OCT imaging at 1-day post-hatch and more marked at 1 year. Spectral domain OCT may provide a reliable end point for therapeutic intervention in this animal model of inherited retinal degeneration.
Veterinary Ophthalmology 05/2013; · 0.75 Impact Factor
-
Clare V Logan,
Barbara Lucke,
Caroline Pottinger,
Zakia A Abdelhamed,
David A Parry,
Katarzyna Szymanska,
Christine P Diggle,
Anne van Riesen,
Joanne E Morgan,
Grace Markham, [......],
Tim Helliwell,
Mariacristina Scoto,
Christoph Hübner,
David T Bonthron,
Graham R Taylor,
Eamonn Sheridan,
Francesco Muntoni,
Ian M Carr,
Markus Schuelke,
Colin A Johnson
[show abstract]
[hide abstract]
ABSTRACT: Infantile myopathies with diaphragmatic paralysis are genetically heterogeneous, and clinical symptoms do not assist in differentiating between them. We used phased haplotype analysis with subsequent targeted exome sequencing to identify MEGF10 mutations in a previously unidentified type of infantile myopathy with diaphragmatic weakness, areflexia, respiratory distress and dysphagia. MEGF10 is highly expressed in activated satellite cells and regulates their proliferation as well as their differentiation and fusion into multinucleated myofibers, which are greatly reduced in muscle from individuals with early onset myopathy, areflexia, respiratory distress and dysphagia.
Nature Genetics 11/2011; 43(12):1189-92. · 35.53 Impact Factor
-
Kamron Khan,
Adam Rudkin,
David A Parry,
Kathryn P Burdon,
Martin McKibbin,
Clare V Logan,
Zakia I A Abdelhamed,
James S Muecke,
Narcis Fernandez-Fuentes,
Kate J Laurie, [......],
Horm Piseth,
Carmel Toomes,
Robert J Casson,
Graham R Taylor,
Michael Hammerton,
Eamonn Sheridan,
Colin A Johnson,
Chris F Inglehearn,
Jamie E Craig,
Manir Ali
[show abstract]
[hide abstract]
ABSTRACT: Anterior segment dysgenesis describes a group of heterogeneous developmental disorders that affect the anterior chamber of the eye and are associated with an increased risk of glaucoma. Here, we report homozygous mutations in peroxidasin (PXDN) in two consanguineous Pakistani families with congenital cataract-microcornea with mild to moderate corneal opacity and in a consanguineous Cambodian family with developmental glaucoma and severe corneal opacification. These results highlight the diverse ocular phenotypes caused by PXDN mutations, which are likely due to differences in genetic background and environmental factors. Peroxidasin is an extracellular matrix-associated protein with peroxidase catalytic activity, and we confirmed localization of the protein to the cornea and lens epithelial layers. Our findings imply that peroxidasin is essential for normal development of the anterior chamber of the eye, where it may have a structural role in supporting cornea and lens architecture as well as an enzymatic role as an antioxidant enzyme in protecting the lens, trabecular meshwork, and cornea against oxidative damage.
The American Journal of Human Genetics 09/2011; 89(3):464-73. · 10.60 Impact Factor
-
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
[show abstract]
[hide abstract]
ABSTRACT: 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.
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.
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).
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.
Investigative ophthalmology & visual science 08/2011; 52(10):7432-40. · 3.43 Impact Factor
-
Manir Ali,
Martin McKibbin,
Adam Booth,
David A Parry,
Payal Jain,
S Amer Riazuddin,
J Fielding Hejtmancik,
Shaheen N Khan,
Sabika Firasat, Mike Shires, [......],
Ivailo Tournev,
Sylvia Cherninkova,
Hussain Jafri,
Yasmin Raashid,
Carmel Toomes,
Jamie Craig,
David A Mackey,
Luba Kalaydjieva,
Sheikh Riazuddin,
Chris F Inglehearn
[show abstract]
[hide abstract]
ABSTRACT: Primary congenital glaucoma (PCG) is an autosomal-recessive condition characterized by high intraocular pressure (IOP), usually within the first year of life, which potentially could lead to optic nerve damage, globe enlargement, and permanent loss of vision. To date, PCG has been linked to three loci: 2p21 (GLC3A), for which the responsible gene is CYP1B1, and 1p36 (GLC3B) and 14q24 (GLC3C), for which the genes remain to be identified. Here we report that null mutations in LTBP2 cause PCG in four consanguineous families from Pakistan and in patients of Gypsy ethnicity. LTBP2 maps to chromosome 14q24.3 but is around 1.3 Mb proximal to the documented GLC3C locus. Therefore, it remains to be determined whether LTBP2 is the GLC3C gene or whether a second adjacent gene is also implicated in PCG. LTBP2 is the largest member of the latent transforming growth factor (TGF)-beta binding protein family, which are extracellular matrix proteins with multidomain structure. It has homology to fibrillins and may have roles in cell adhesion and as a structural component of microfibrils. We confirmed localization of LTBP2 in the anterior segment of the eye, at the ciliary body, and particularly the ciliary process. These findings reveal that LTBP2 is essential for normal development of the anterior chamber of the eye, where it may have a structural role in maintaining ciliary muscle tone.
The American Journal of Human Genetics 05/2009; 84(5):664-71. · 10.60 Impact Factor
