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H244R VSX1 Is Associated with Selective Cone ON Bipolar Cell Dysfunction and Macular Degeneration in a PPCD Family

¹From the Laboratoire de Biochimie et Génétique Moléculaire, Hôpital Cochin, Paris, France; the ²Institut Cochin, Département de Génétique, Développement et Pathologie Moléculaire, Institut National de la Santé et de la Recherche Médicale (INSERM)-U567, Paris, France; the ³Unité INSERM 592-Université Paris 7, Hôpital Lariboisière–Saint Louis, Paris, France; the ⁴Service d’Ophtalmologie, Centre Hospitalo-Universitaire de Poitiers, France; and the ⁵Service d’Ophtalmologie, Hôpital Hôtel-Dieu, Paris, France.

PURPOSE. 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.

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