Eye diseases are a common cause of human disability and many of them are inherited. We study genetic disorders affecting the front of the eye, the so called anterior segment dysgenesis. These include congenital as well as adult-onset conditions and include abnormalities of the cornea, iris, trabecular meshwork and lens. We are currently working on, or have worked on, sclerocornea, microcornea with corneal opacity, corneal hereditary endothelial dystrophy, FUCHS endothelial dystrophy, keratoconus, cataracts and glaucoma. Most of our work to date has been on families of Pakistani origin, both in Yorkshire and in Northern Pakistan. To identify the genes and proteins involved, we carry out genetic analysis of families in which the parents are related, sequentially applying techniques for autozygosity mapping (see http://autozygosity.org), bioinformatics and gene sequencing. We also carry out functional characterization of the proteins identified using methods such as reverse transcription PCR, in situ hybridisation, immunohistochemistry, siRNA and gene transfer.
In another research strand, we also study three strains of blind chickens (retinopathy globe enlarged, retinal dysplasia and degeneration and blindness enlarged globe), which arose naturally in Scottish farm stocks. To these, we apply similar genetic methods to locate and identify the defective genes and then search for mutations causing similar conditions in human patients. More recently, we have also explored the use of these birds as models for the study of emmetropisation, the process of coordination between eye growth and image focus.
Figure 1. Anterior image of patient with congenital cataract and corneal opacity
Figure 2. DNA sequence analysis of the PXDN gene in this patient.
Khan K, Logan CV, McKibbin M, Sheridan E, Elçioglu NH, Yenice O, Parry DA, Fernandez-Fuentes N, Abdelhamed ZI, Al-Maskari A, Poulter JA, Mohamed MD, Carr IM, Morgan JE, Jafri H, Raashid Y, Taylor GR, Johnson CA, Inglehearn CF, Toomes C, Ali M. (2012) Next generation sequencing identifies mutations in Atonal homolog 7 (ATOH7) in families with global eye developmental defects. Hum Mol Genet. 21, 776-783.
Khan K, Rudkin A, Parry DA, Burdon KP, McKibbin M, Logan CV, Abdelhamed ZI, Muecke JS, Fernandez-Fuentes N, Laurie KJ, Shires M, Fogarty R, Carr IM, Poulter JA, Morgan JE, Mohamed MD, Jafri H, Raashid Y, Meng N, Piseth H, Toomes C, Casson RJ, Taylor GR, Hammerton M, Sheridan E, Johnson CA, Inglehearn CF, Craig JE, Ali M. (2011) Homozygous mutations in PXDN cause congenital cataract, corneal opacity, and developmental glaucoma. Am J Hum Genet. 89, 464-473.
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. Invest Ophthalmol Vis Sci. 52, 7432-7440.