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Human Molecular Genetics, 2001, Vol. 10, No. 21 2415-2423
© 2001 Oxford University Press

Missense mutations in COL8A2, the gene encoding the {alpha}2 chain of type VIII collagen, cause two forms of corneal endothelial dystrophy

Susmito Biswas1,2, Francis L. Munier3,4, Jill Yardley2, Niki Hart-Holden2, Rahat Perveen2, Pascal Cousin4, John E. Sutphin5, Bruce Noble6, Mark Batterbury7, Cay Kielty8, Anna Hackett9, Richard Bonshek1, Alan Ridgway1, David McLeod1, Val C. Sheffield5, Edwin M. Stone5, Daniel F. Schorderet4 and Graeme C. M. Black1,2,+

1Academic Department of Ophthalmology, Manchester Royal Eye Hospital, Oxford Road, Manchester M13 9WH, UK, 2University Department of Molecular Genetics and Regional Genetics Service, St Mary’s Hospital, Hathersage Road, Manchester M13 0JH, UK, 3Hôpital Jules Gonin, Avenue de France, Lausanne CH 1004, Switzerland, 4Division Autonome de Génétique Médicale, CHUV, Lausanne CH 1011, Switzerland, 5Department of Ophthalmology and Visual Sciences, The University of Iowa College of Medicine, 200 Hawkins Drive, Iowa City, IA, USA, 6Department of Ophthalmology, The General Infirmary at Leeds, Belmont Grove, Leeds, West Yorkshire LS2 9NS, UK, 7Department of Ophthalmology, Royal Liverpool University Hospital, Liverpool, UK, 8School of Medicine, University of Manchester, Oxford Road, Manchester, UK, 9Hunter Genetics, PO Box 84, Waratah, Newcastle, NSW 2291, Australia

Corneal clarity is maintained by its endothelium, which functions abnormally in the endothelial dystrophies, leading to corneal opacification. This group of conditions includes Fuchs’ endothelial dystrophy of the cornea (FECD), one of the commonest indications for corneal transplantation performed in developed countries, posterior polymorphous dystrophy (PPCD) and the congenital hereditary endothelial dystrophies (CHED). A genome-wide search of a three-generation family with early-onset FECD demonstrated significant linkage with D1S2830 (Zmax = 3.72, {theta} = 0.0). Refinement of the critical region defined a 6–7 cM interval of chromosome 1p34.3–p32 within which lies the COL8A2 gene. This encodes the 703 amino acid {alpha}2 chain of type VIII collagen, a short-chain collagen which is a component of endothelial basement membranes and which represented a strong candidate gene. Analysis of its coding sequence defined a missense mutation (gln455lys) within the triple helical domain of the protein in this family. Mutation analysis in patients with FECD and PPCD demonstrated further missense substitutions in familial and sporadic cases of FECD as well as in a single family with PPCD. This is the first description of the molecular basis of any of the corneal endothelial dystrophies or of mutations in type VIII collagen in association with human disease. This suggests that the underlying pathogenesis of FECD and PPCD may be related to disturbance of the role of type VIII collagen in influencing the terminal differentiation of the neural crest derived corneal endothelial cell.

+ To whom correspondence should be addressed at: Department of Clinical Genetics, St Mary’s Hospital, Hathersage Road, Manchester M13 0JH, UK. Tel: +44 161 276 6094; Fax: +44 161 276 6145; Email: gblack@man.ac.uk


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