Abstract
Purpose :
Mutations in retinal secreted serine protease PRSS56 and transmembrane glycoprotein MFRP, a factor predominantly expressed in the retinal pigment epithelium (RPE) constitute major causes of nanophthalmos, a condition characterized by severe reduction in ocular axial length/extreme hyperopia. Interestingly, common variants of these genes have been implicated in myopia, a condition associated with ocular axial elongation. In fact, mice with loss of function mutation in PRSS56 or MFRP exhibit a reduction in ocular axial length. We found that Adamts19 expression is significantly upregulated in the retina of mice lacking either Prss56 or Mfrp. Here, we test the hypothesis that retinal Adamts19 upregulation compensates for lack of PRSS56 or MFRP in supporting ocular axial growth. Additionally, we test the requirement of Prss56 or Mfrp in supporting excessive ocular elongation caused by a null mutation in the gene coding for Interphotoreceptor retinoid-binding protein (IRBP).
Methods :
We crossed Prss56 or Mfrp mutant mice with mice deficient in Adamts19 to determine the effect of Adamts19 inactivation on ocular size reduction caused by loss of Prss56 or Mfrp function. In parallel, Prss56 and Mfrp mutant mice were crossed to Irbp deficient mice. A detailed ocular biometric ocular assessment was conducted on the progeny of various genotypes using the SD-OCT.
Results :
Ocular axial length and vitreous chamber depth (VCD) exhibited a significantly greater reduction in double mutants (Prss56-/-;Adamts19-/- or Mfrp-/-;Adamts19-/- ) as compared to respective Prss56 or Mfrp single mutants. Overall, we demonstrate that while ADAMTS19 is not required for ocular growth during normal development, its inactivation exacerbates ocular axial length reduction in Prss56 and Mfrp mutant mice. Furthermore, we demonstrate that inactivation of either Prss56 or Mfrp prevented ocular axial elongation in Irbp mutant mice (Irbp-/-;Prss56-/- and Irbp-/-;Mfrp-/-, respectively). Thus, both PRSS56 and MFRP are necessary for supporting excessive ocular elongation due to a null mutation in Irbp.
Conclusions :
We identified ADAMTS19 as a novel factor involved in ocular size regulation and demonstrate that the retinal Adamts19 upregulation is part of an adaptive response to overcome impaired ocular growth. Furthermore, our findings support a role for molecular crosstalk between the retina and RPE involved in refractive development.
This is a 2021 ARVO Annual Meeting abstract.