VSX1: a gene for posterior polymorphous dystrophy and keratoconus.
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.
Héon
Elise
E
Cellular and Molecular Division, Toronto Western Research Institute, Toronto Western Hospital, 399 Bathurst Street, Toronto, Ontario, Canada M5T 2S8. eheon@uhnres.utoronto.ca
Greenberg
Alex
A
Kopp
Kelly K
KK
Rootman
David
D
Vincent
Andrea L
AL
Billingsley
Gail
G
Priston
Megan
M
Dorval
Kimberley M
KM
Chow
Robert L
RL
McInnes
Roderick R
RR
Heathcote
Godfrey
G
Westall
Carol
C
Sutphin
John E
JE
Semina
Elena
E
Bremner
Rod
R
Stone
Edwin M
EM
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D002648:Child; D004252:DNA Mutational Analysis; D004596:Electroretinography; D005136:Eye Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005642:Fuchs' Endothelial Dystrophy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007223:Infant; D007640:Keratoconus / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D018807:Polymorphism, Single-Stranded Conformational; D012160:Retina / Q000378:metabolism / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017386:Sequence Homology, Amino Acid
D005136:Eye Proteins; D018398:Homeodomain Proteins; C491583:VSX1 protein, human