Autosomal-Recessive Posterior Microphthalmos Is Caused by Mutations in PRSS56, a Gene Encoding a Trypsin-Like Serine Protease

Abstract

Posterior microphthalmos (MCOP) is a rare isolated developmental anomaly of the eye characterized by extreme hyperopia due to short axial length. The population of the Faroe Islands shows a high prevalence of an autosomal-recessive form (arMCOP) of the disease. Based on published linkage data, we refined the position of the disease locus (MCOP6) in an interval of 250 kb in chromosome 2q37.1 in two large Faroese families. We detected three different mutations in PRSS56. Patients of the Faroese families were either homozygous for c.926G>C (p.Trp309Ser) or compound heterozygous for c.926G>C and c.526C>G (p.Arg176Gly), whereas a homozygous 1 bp duplication (c.1066dupC) was identified in five patients with arMCOP from a consanguineous Tunisian family. In one patient with MCOP from the Faroe Islands and in another one from Turkey, no PRSS56 mutation was detected, suggesting nonallelic heterogeneity of the trait. Using RT-PCR, PRSS56 transcripts were detected in samples derived from the human adult retina, cornea, sclera, and optic nerve. The expression of the mouse ortholog could be first detected in the eye at E17 and was maintained into adulthood. The predicted PRSS56 protein is a 603 amino acid long secreted trypsin-like serine peptidase. The c.1066dupC is likely to result in a functional null allele, whereas the two point mutations predict the replacement of evolutionary conserved and functionally important residues. Molecular modeling of the p.Trp309Ser mutant suggests that both the affinity and reactivity of the enzyme toward in vivo protein substrates are likely to be substantially reduced.

Spectral domain optical coherence tomography findings in retinal folds associated with posterior microphthalmos

“…6 The gene was found in retinal tissue; in the mouse retina it was reported to be strongly expressed in retinal ganglion cells, moderately expressed in the inner nuclear layer, and expressed at a low level in the outer nuclear layer.…”

Loss of Zebrafish Mfrp Causes Nanophthalmia, Hyperopia, and Accumulation of Subretinal Macrophages

“…Interestingly, Mfrp mutations have been associated with altered levels of Prss56, a serine protease associated with angle-closure glaucoma, posterior microphthalmia, and myopia in humans. 41–44 …”

Genetics of Refraction and Myopia

“…Several loci for high hyperopia have been mapped, including NNO1 (OMIM 600165) at chromosome 11p for autosomal-dominant nanophthalmos, 6 MFRP of NNO2 (OMIM 606227) at chromosome 11q23.3 for autosomal-recessive nanophthalmos, 10 NNO3 (OMIM 611897) at chromosome 2q11-q14 for autosomal-dominant congenital simple microphthalmia, 11 TMEM98 of NNO4 (OMIM 615949) at chromosome 17p12-q12 for autosomaldominant nanophthalmos, 12,13 and PRSS56 (OMIM 613858) at chromosome 2q37.1 for autosomal-recessive posterior microphthalmos. 14,15 Families with physiologic high hyperopia are not uncommon, but the loci or genes responsible for them are yet to be identified.…”