H244R VSX1 is associated with selective cone ON bipolar cell dysfunction and macular degeneration in a PPCD family.
OBJECTIVE
To elucidate the retinal dysfunction and the molecular basis of posterior polymorphous corneal dystrophy (PPCD) associated with macular dystrophy, both inherited in a dominant manner through a three-generation family.


METHODS
Ophthalmologic examinations including slit lamp examination, visual acuity tests, fundus visualization by scanning laser ophthalmoscopy, fluorescein angiography, color vision tests, electro-oculography, photopic and scotopic electroretinography (ERG) according to the International Society for Clinical Electrophysiology of Vision (ISCEV) protocols, and oscillatory potential (OP) recordings were conducted on affected family members. Corneal button from one affected patient was examined by transmission electron microscopy. All exons and intron-exon boundaries of the VSX1 and the COL8A2 genes were amplified by polymerase chain reaction and sequenced.


RESULTS
The presence of endothelial cells that have epithelial-like features with multiple layers, desmosomal junctions, and microvillous projections supports the diagnosis of PPCD. Sequence analysis indicated that the H244R variant in the VSX1 segregated with corneal and macular disease phenotypes in this family. Electrophysiologic studies indicated normal scotopic ERG findings, decreased amplitude of the photopic b-wave, photopic OP2 and OP3 barely recordable with a preserved OP4 amplitude, and variably decreased 30-Hz flicker amplitude.


CONCLUSIONS
The human VSX1 is required for cone ON bipolar cell function but not for rod and cone OFF bipolar cells, giving a unique example of such a selective heritable retinal defect in humans. Furthermore, the authors provide the first clinical support for a new alternative role of VSX1 in cone biology, probably similar to that proposed for its goldfish ortholog during retinal differentiation.
Valleix
Sophie
S
Laboratoire de Biochimie et Génétique Moléculaire, Hôpital Cochin, Paris, France. sophie.valleix@cch.ap-hop-paris.fr
Nedelec
Brigitte
B
Rigaudiere
Florence
F
Dighiero
Paul
P
Pouliquen
Yves
Y
Renard
Gilles
G
Le Gargasson
Jean-François
JF
Delpech
Marc
M
D000328:Adult; D024102:Collagen Type VIII / Q000235:genetics; D003315:Cornea / Q000648:ultrastructure; D003317:Corneal Dystrophies, Hereditary / Q000150:complications / Q000175:diagnosis / Q000235:genetics*; D004585:Electrooculography; D004596:Electroretinography; D005136:Eye Proteins / Q000235:genetics*; D005260:Female; D005451:Fluorescein Angiography; D005799:Genes, Dominant; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D008268:Macular Degeneration / Q000150:complications / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D016133:Polymerase Chain Reaction; D051245:Retinal Bipolar Cells / Q000473:pathology*; D017949:Retinal Cone Photoreceptor Cells / Q000473:pathology*
C443712:COL8A2 protein, human; D024102:Collagen Type VIII; D005136:Eye Proteins; D018398:Homeodomain Proteins; C491583:VSX1 protein, human