Vision Research Group: Anterior Segment Dysgenesis

Group Leader: Dr Manir Ali, Senior Research Fellow
medma@leeds.ac.uk

Understanding the genetic basis of inherited eye disease

Eye diseases are a common cause of human disability and many of them are inherited. In order to identify the genes and proteins involved in these conditions, we carry out genetic analysis of families sequentially applying techniques of linkage analysis, next generation sequencing and bioinformatics.

For families, in which the affected individuals have parents who are related we apply autozygosity mapping (see http://www.autozygosity.org/). Most of our work to date has been on families of Pakistani origin, both in Yorkshire and in Northern Pakistan where there is a high degree of consanguinity. When a mutation is identified this information is relayed back to the patient through their doctor so that they can be informed of their choices and expected outcomes. The eye conditions that we are currently studying include microphthalmia, cataract, sclerocornea, micorcornea, corneal opacity, Fuchs endothelial dystrophy, keratoconus, glaucoma and retinal dystrophies (in collaboration with Professor Chris Inglehearn and Dr Carmel Toomes).

We have also recently started to work on the genetic analysis of neurological and psychotic disorders (in collaboration with Professor Chris Inglehearn and Dr Steve Clapcote (in Faculty of Biological Sciences)). Other techniques that we use in the laboratory for the functional characterization of proteins include western blotting, immunohistology, confocal microscopy, molecular cloning and site-directed mutagenesis, as well as bacterial and mammalian cell culturing.

There are few effective treatments for the retinal diseases and the search for new therapies is greatly helped when animals with the same disease are available. Hence we are also characterising three lines of blind chickens (retinopathy globe enlarged, retinal dysplasia and degeneration and blindness enlarged globe) in collaboration with Dr Paul Hocking (Roslin Institute, Edinburgh). In these, we use similar genetic analyses to locate and identify the defective gene then look for mutations causing a similar condition in human patients. These chicken models will serve as a resource for testing new therapies.

Congenital Cataract

Figure 1. Anterior image of patient with congenital cataract and corneal opacity

People

Dr Manir Ali - Group Leader, Senior Research Fellow
Ms Layal Abi Farraj - PhD Student
Mr Mohammed El-Asrag - PhD Student
Dr Salina Siddiqui - Clinical Research Fellow
Mr Ahmed Al-Amri - PhD Student

Publications

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, 464-73.

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.

Ali M, Buentello-Volante B, McKibbin M, Rocha-Medina JA, Fernandez-Fuentes N, Koga-Nakamura W, Ashiq A, Khan K, Booth AP, Raashid Y, Jafri H, Rice A, Inglehearn CF, Zenteno JC. (2010) Homozygous FOXE3 mutations cause non-syndromic, bilateral, total sclerocornea, aphakia, microphthalmia and optic disc coloboma. Mol Vis. 16, 1162-1168.

Ali M, McKibbin M, Booth AP, Parry DA, Jain P, Riazuddin SA, Hejmancik JF, Khan SN, Firasat S, Shires M, Gilmour DF, Towns K, Murphy A-L, Azmanov D, Tournev I, Cheminkova S, Jafri H, Rashid Y, Toomes C, Craig J, Mackey DA, Kalaydjieva L, Riazuddin S, Inglehearn CF. (2009) Null mutations in LTBP2 cause Primary Congenital Glaucoma. Am J Hum Genet. 84, 664-671.

Funding

EU-Initial Training Networks, FP7-PEOPLE-2012-ITN, Co-Applicant. EyeTN - Beyond the Genome; training the next generation of ophthalmic researchers. Apr 2013 – Mar 2017.

Fight For Sight, PhD Studentship, Co-Applicant. Determining the genetic basis of keratoconus and implications for treatment. Jan 2012 – Dec 2014.

Yorkshire Eye Research, Project Grant, PI. Testing the effectiveness of premature stop codon bypass reagents in retinal explant cultures. Jan 2012 – June 2013.

Yorkshire Eye Research Project Grant, Co-Applicant. BOSU: Incidence of young onset corneal dystrophy in the UK. Nov 2011 – Oct 2013.

Medical Research Council, Clinical Research Training Fellowship for Ms. Salina Siddiqui, Supervisor. Genetics analysis of corneal endothelial dystrophies. Sep 2011 – Aug 2014.

Wellcome Trust, Clinical Research Training Fellowship for Mr. Kamron Khan, Supervisor. Genetics of congenital cataract-microcornea syndrome. Apr 2010 – Mar 2013.

Studentships

Competitive fully funded PhD scholarships are available within the Faculty Graduate School.

Self-funded students are always welcomed to apply for postgraduate study. International students must meet the entry requirements for English. Bench fees are required.

Please email medma@leeds.ac.uk for informal enquiries.

Useful Websites

http://www.erdc.info/