A novel bA3/A1-crystallin gene mutation results in persistent fetal vasculature

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DESCRIPTION (provided by applicant): Persistent fetal vasculature (PFV) is a human disease that results from a failure of the fetal vasculature to regress. It is a common congenital developmental disorder of the eye found in an otherwise normal child. The underlying cause of PFV disease is not well understood. We previously described a naturally occurring mutation (Nuc1) in the Sprague-Dawley rat with a novel eye phenotype involving cataract, retention of fetal vasculature, and developmental abnormalities in the retina. In Nuc1 there is failure of regression of the entire fetal intraocular vasculature and not just part of it, as reported in several other mouse models of PFV. We recently reported that the mutation causing Nuc1 is a 27 base pair insertion in exon 6 of the 2A3/A1-crystallin gene on rat chromosome 10. The 27 base pair insertion is composed of near-perfect tandem repeats of a 7 base pair sequence, TGACTAT. This in-frame insertion results in the loss of a universally conserved glycine residue in exon 6 and its replacement with 10 new amino acids. We demonstrated that in the neural retina, 2A3/A1-crystallin is expressed only in the astrocyes. In the Nuc1 rat, astrocytes surround the retained vessels as is found in other animal models of PFV. However, astrocytes are not associated with the hyaloid vasculature in the normal eye. While 2A3/A1-crystallin is entirely cytoplasmic in lens, the protein is largely nuclear in astrocytes. Both lens fibers and astrocytes from Nuc1 homozygotes show striking structural abnormalities with profound effects on the expression and organization of intermediate filaments (IFs). We have demonstrated that both the astrocytes associated with the fetal vasculature and the lenses in Nuc1 rats and PFV patients express increased amounts of VEGF. Based on these findings, we hypothesize that mutation of 2A3/A1- crystallin causes abnormal association of astrocytes with the hyaloid artery, which inhibits regression of the fetal vasculature. To test this hypothesis, the following specific aims are proposed: AIM1: To characterize and compare 2A3/A1-crystallin expression in wildtype and in Nuc1 homozygous rats during lens fiber cell and astrocyte development. AIM2: To investigate if altered motility of Nuc1 homozygous astrocytes during development contributes to the abnormal association between astrocytes and the hyaloid vasculature. AIM3: To determine if VEGF produced by astrocytes expressing mutant 2A3/A1-crystallin mediates the survival and stabilization of the hyaloid vasculature in the Nuc1 rat. We believe that the proposed studies should provide new insights into the cellular and molecular interactions that regulate hyaloid vascular regression. The possibility that 2A3/A1-crystallin may have a role in hyaloid vascular regression is important; it may help elucidate mechanisms underlying PFV that would have potential clinical implications. PUBLIC HEALTH RELEVANCE: Persistent Fetal Vasculature (PFV) is a common blinding, congenital eye disease. Our data (published and unpublished) indicate that mutant 2A3/A1-crystallin plays a role in PFV. The proposed studies may help elucidate mechanisms underlying PFV that would have potential therapeutic implications.