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Human Molecular Genetics, 2002, Vol. 11, No. 9 1029-1036
© 2002 Oxford University Press

VSX1: A gene for posterior polymorphous dystrophy and keratoconus

Elise Héon1,2,3,4,*, Alex Greenberg3, Kelly K. Kopp8, David Rootman2, Andrea L. Vincent2,3, Gail Billingsley1,2, Megan Priston1, Kimberley M. Dorval3,5, Robert L. Chow2,7, Roderick R. McInnes2,3,6,7, Godfrey Heathcote10, Carol Westall2,3, John E. Sutphin8, Elena Semina9, Rod Bremner1,3,4,5 and Edwin M. Stone8

1Cellular and Molecular Division, Toronto Western Research Institute, Toronto, Canada M5T 2S8, 2Department of Ophthalmology, The Hospital for Sick Children Research Institute, The Hospital for Sick Children, Toronto, Canada M5G 1X8, 3Vision Science Research Program, Toronto Western Hospital, Toronto, Canada M5T 2S8, 4Department of Ophthalmology, 5Department of Laboratory Medicine and Pathobiology, 6Department of Pediatrics, 7Department of Molecular and Medical Genetics, University of Toronto, Toronto, Canada M5S 1A8, 8Department of Ophthalmology, 9Department of Pediatrics, The University of Iowa Hospitals and Clinics, Iowa City 52242, USA, 10Department of Pathology and Department of Ophthalmology, The University of Western Ontario, London, Canada N6A 4V2.

We identified mutations in the VSX1 homeobox gene for two distinct inherited corneal dystrophies; posterior polymorphous dystrophy (PPD) and keratoconus. One of the mutation (R166W) responsible for keratoconus altered the homeodomain and impaired DNA binding. Two other sequence changes (L159M and G160D) were associated with keratoconus and PPD, respectively, and involved a region adjacent to the homeodomain. The G160D substitution, and a fourth defect affecting the highly conserved CVC domain (P247R), occurred in a child with very severe PPD who required a corneal transplant at 3 months of age. In this family, relatives with the G160D change alone had mild to moderate PPD, while P247R alone caused no corneal abnormalities. However, with either the G160D or P247R mutation, electroretinography detected abnormal function of the inner retina, where VSX1 is expressed. These data define the molecular basis of two important corneal dystrophies and reveal the importance of the CVC domain in the human retina.

* To whom correspondence should be addressed at: Room 6-412, Toronto Western Hospital, 399 Bathurst Street, Toronto, Ontario, Canada M5T 2S8. Tel: +1 416 603 5418; Fax: +1 416 603 5126. Email: eheon{at}uhnres.utoronto.ca


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