Understanding the causes of human visual defects.
Our work aims to determine the causes of human visual defects and to find out more about normal eye function. Ultimately we aim to contribute to the search for cures for blinding diseases.
One major area of research is in homozygosity mapping to identify mutations causing recessively inherited diseases. We carried out an empirical investigation of the theoretical basis of this technique (Reference 2 below) and used it to identify a strong candidate for the LCA5 gene (Figure 1), defective in Lebers congenital amaurosis (blindness at or shortly after birth). In addition we played a major role in an international collaboration which identified SLC4A11 as the defective gene in corneal hereditary endothelial dystrophy (Figure 2 and Reference 1).
Figure 1 Human retinal section stained with an antibody to the LCA5 gene
Another interest for the group lies in the study of complex diseases of vision. A whole genome linkage search was carried out in large families with strabismus (squint), a trait affecting approximately 1 in 25 people and often leading to blindness in one eye. In addition we took part in an international collaboration to identify susceptibility genes for myopia, a condition reaching near epidemic proportions in many Asian countries (Reference 3).
We also continued our ongoing interest in determining the cellular basis for splicing factor retinitis pigmentosa. Finally, we sought to translate research findings into a clinical setting by piloting a diagnostic service for inherited retinal diseases, in collaboration with clinical colleagues.
Figure 2 Congenital hereditary corneal dystrophy with characteristic uniform ground glass edema from limbus to center of cornea
Vithana EN, Morgan P, Sundaresan P, Ebenezer ND, Tan DT, Mohamed MD, Anand S, Khine KO, Venkataraman D, Yong VH, Salto-Tellez M, Venkatraman A, Guo K, Hemadevi B, Srinivasan M, Prajna V, Khine M, Casey JR, Inglehearn CF, Aung T. Mutations in sodium-borate cotransporter SLC4A11 cause recessive congenital hereditary endothelial dystrophy (CHED2). Nat Genet. 2006;38(7):755-7.
den Hollander AI, Koenekoop RK, Mohamed MD, Arts HH, Boldt K, Towns KV, Sedmak T, Beer M, Nagel-Wolfrum K, McKibbin M, Dharmaraj S, Lopez I, Ivings L, Williams GA, Springell K, Woods CG, Jafri H, Rashid Y, Strom TM, van der Zwaag B, Gosens I, Kersten FF, van Wijk E, Veltman JA, Zonneveld MN, van Beersum SE, Maumenee IH, Wolfrum U, Cheetham ME, Ueffing M, Cremers FP, Inglehearn CF, Roepman R (2007). Mutations in LCA5, encoding the ciliary protein lebercilin, cause Leber congenital amaurosis. Nat Genet 39:889-95.
Boon KL, Grainger RJ, Ehsani P, Barrass JD, Auchynnikava T, Inglehearn CF, Beggs JD (2007). Prp8 mutations that cause human retinitis pigmentosa lead to a U5 snRNP maturation defect in yeast. Nat Struct Mol Biol; [Epub ahead of print]