Variants in myelin regulatory factor (MYRF) cause autosomal dominant nanophthalmos.

Abstract

Purpose : Nanophthalmos is part of a spectrum of genetic disorders, characterized by a small structurally normal eye. A large 5-generation family with autosomal dominant nanophthalmos was previously identified and mapped to the NNO1 locus on chromosome 11. Here, we evaluate myelin regulatory factor (MYRF) as a candidate gene for nanophthalmos and uncover its role in eye development.

Methods : We used combined linkage and pooled exome sequencing approaches to fine map and sequence coding genes in the NNO1 locus. A pooled sample of all affected individuals and a subtractive pool of unaffected individuals were enriched for the exome and sequenced using the IlluminaHighSeq platform. Sixty unrelated probands were screened for variants in MYRF, and a syndromic patient carrying an MYRF mutation underwent ophthalmic examination. To validate the most promising candidate gene, Myrf conditional knockout mice were generated using the Rx promoter to inactivate Myrf in the early retina and retinal pigment epithelium. Mouse eyes were analyzed by histology and immunohistochemistry.

Results : Of three candidate variants within the 3.5 Mb non-recombinant interval on chromosome 11q12 between D11S4191 and D11S188, the MYRF c.3376-1G>A (p.Gly1126Valfs*31) splice site mutation was the most promising, as the MYRF gene was expressed in the eye and had an unknown eye phenotype. One unrelated syndromic child carrying an MYRF mutation was found to have axial hyperopia (+7.0D, 17 mm eye). No other mutations were found in 60 unrelated nanophthalmos/high hyperopia probands. The phenotype in Myrf conditional knockout mice revealed patchy loss of pigmentation of the retinal pigment epithelium and retinal degeneration. Eyes from Myrf knockout mice had decreased levels and altered localization of TMEM98, a known nanophthalmos gene. Furthermore, MYRF was found to directly interact with TMEM98 by co-immunoprecipitation experiments.

Conclusions : Our results suggest that rare variants in MYRF cause autosomal dominant isolated and syndromic nanophthalmos. They have potential implications for counseling of the NNO1 family and syndromic MYRF patients. Furthermore, our studies enhance our understanding of eye growth and development by identifying a new gene and new pathway, which may ultimately lead to new therapies for refractive error.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.